Cetuximab versus methotrexate in first-line treatment of older, frail patients with inoperable recurrent or metastatic head and neck cancer (ELAN UNFIT): a randomised, open-label, phase 3 trial.

BACKGROUND: At present, there is no established standard treatment for frail older patients with recurrent or metastatic head and neck squamous cell carcinoma. We aimed to compare the efficacy and safety of cetuximab to those of methotrexate (the reference regimen) in this population. METHODS: This randomised, open-label, phase 3 trial was done at 20 hospitals in France. Patients aged 70 years or older, assessed as frail by the ELAN Geriatric Evaluation, with recurrent or metastatic head and neck squamous cell carcinoma in the first-line setting and with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 were eligible for inclusion. Patients were randomly assigned (1:1) to receive cetuximab 500 mg/m2 intravenously every 2 weeks or methotrexate 40 mg/m2 intravenously every week, with minimisation by ECOG performance status, type of disease evolution, Charlson Comorbidity Index score, serum albumin concentration, and geriatrician consultation. To avoid deterministic minimisation and assure allocation concealment, patients were allocated with a probability of 0·80 to the treatment that most reduced the imbalance. Treatment was continued until disease progression or unacceptable toxicity, whichever occurred first. The primary endpoint was failure-free survival (defined as the time from randomisation to disease progression, death, discontinuation of treatment, or loss of 2 or more points on the Activities in Daily Living scale, whichever occurred first) and was analysed in the intention-to-treat population. 151 failures expected out of 164 patients were required to detect a hazard ratio (HR) of 0·625 with 0·05 alpha error, with 80% power. A futility interim analysis was planned when approximately 80 failures were observed, based on failure-free survival. Safety analyses included all patients who received at least one dose of the study drug. This study is registered on ClinicalTrials.gov (NCT01884623) and was stopped for futility after the interim analysis. FINDINGS: Between Nov 7, 2013, and April 23, 2018, 82 patients were enrolled (41 to the cetuximab group and 41 to the methotrexate group); 60 (73%) were male, 37 (45%) were aged 80 years or older, 35 (43%) had an ECOG performance status of 2, and 36 (44%) had metastatic disease. Enrolment was stopped for futility at the interim analysis. At the final analysis, median follow-up was 43·3 months (IQR 30·8-52·1). At data cutoff, all 82 patients had failure; failure-free survival did not differ significantly between the groups (median 1·4 months [95% CI 1·0-2·1] in the cetuximab group vs 1·9 months [1·1-2·6] in the methotrexate group; adjusted HR 1·03 [95% CI 0·66-1·61], p=0·89). The frequency of patients who had grade 3 or worse adverse events was 63% (26 of 41) in the cetuximab group and 73% (30 of 41) in the methotrexate group. The most common grade 3-4 adverse events in the cetuximab group were fatigue (four [10%] of 41 patients), lung infection (four [10%]), and rash acneiform (four [10%]), and those in the methotrexate group were fatigue (nine [22%] of 41), increased gamma-glutamyltransferase (seven [17%]), natraemia disorder (four [10%]), anaemia (four [10%]), leukopenia (four [10%]), and neutropenia (four [10%]). The frequency of patients who had serious adverse events was 44% (18 of 41) in the cetuximab group and 39% (16 of 41) in the methotrexate group. Four patients presented with a fatal adverse event in the cetuximab group (sepsis, decreased level of consciousness, pulmonary oedema, and death of unknown cause) as did two patients in the methotrexate group (dyspnoea and death of unknown cause). INTERPRETATION: The study showed no improvement in failure-free survival with cetuximab versus methotrexate. Patients with an ECOG performance status of 2 did not benefit from these systemic therapies. New treatment options including immunotherapy should be explored in frail older patients with recurrent or metastatic head and neck squamous cell carcinoma, after an initial geriatric evaluation, such as the ELAN Geriatric Evaluation. FUNDING: French programme PAIR-VADS 2011 (sponsored by the National Cancer Institute, the Fondation ARC and the Ligue Contre le Cancer), GEMLUC, GEFLUC, and Merck Santé. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.

Central venous catheter associated upper extremity deep vein thrombosis in cancer patients: Diagnosis and therapeutic management.

Catheter-related thrombosis (CRT) is a relatively frequent and potentially fatal complication arising in patients with cancer who require a central catheter placement for intravenous treatment. In everyday practice, CRT remains a challenge for management; despite its frequency and its negative clinical impact, few data are available concerning diagnosis and treatment of CRT. In particular, no diagnostic studies or clinical trials have been published that included exclusively patients with cancer and a central venous catheter (CVC). For this reason, many questions regarding optimal management of CRT remain unanswered. Due to the paucity of high-grade evidence regarding CRT in cancer patients, guidelines are derived from upper extremity DVT studies for diagnosis, and from those for lower limb DVT for treatment. This article addresses the issues of diagnosis and management of CRT through a review of the available literature and makes a number of proposals based on the available evidence. In symptomatic patients, venous ultrasound is the most appropriate choice for first-line diagnostic imaging of CRT because it is noninvasive, and its diagnostic performance is high (which is not the case in asymptomatic patients). In the absence of direct comparative clinical trials, we suggest treating patients with CRT with a therapeutic dose of either a LMWH or a direct oral factor Xa inhibitor, with or without a loading dose. These anticoagulants should be given for a total of at least three months, including at least one month after catheter removal following initiation of therapy.

Treatment of cancer-associated venous thromboembolism in patients under palliative care.

Many patients with cancer require palliative care at some stage and the vast majority of people followed in palliative care are cancer patients. Patients with cancer are at high risk of venous thromboembolism (VTE), and this is particularly true during the advanced palliative phase when mobility is limited or absent. Patients with cancer in palliative cancer are at higher bleeding risk compared to non-cancer patients. Decisions to treat VTE or withhold anticoagulation for these patients have proven to be difficult and depend largely on an individual clinician's judgment. For this reason, we have developed a consensus proposal for appropriate management of cancer-associated thromboembolism (CAT) in patients in palliative care, which is presented in this article. The proposal was informed by the recent scientific literature retrieved through a systematic literature review. In cancer patients in advanced palliative care, the benefit-risk ratio of anticoagulation seems unfavourable with a higher haemorrhagic risk than the benefit associated with prevention of CAT recurrence and, above all, in the absence of any benefit on quality of life. For this reason, we recommend that patients should be prescribed anticoagulants on a case-by-case basis. The choice of whether to treat, and with which type of treatment, should take into account anticipated life expectancy and patient preferences, as well as clinical factors such as the estimated bleeding risk, the type of VTE experienced and the time since the VTE event.

Three-Month Outcomes in Cancer Patients with Superficial or Deep Vein Thrombosis in the Lower Limbs: Results from the RIETE Registry.

BACKGROUND: The clinical characteristics and outcomes of cancer patients with lower-limb isolated superficial vein thrombosis (SVT) have not been consistently evaluated. METHODS: We used data in the RIETE registry to compare the clinical characteristics and 90-day outcomes for patients with: (1) active cancer and lower-limb SVT; (2) active cancer and lower-limb deep vein thrombosis (DVT); (3) lower-limb SVT without cancer. The primary outcomes included subsequent symptomatic SVT, DVT or pulmonary embolism (PE). Secondary outcomes were major bleeding and death. RESULTS: From March 2015 to April 2021, there were 110 patients with cancer and SVT, 1695 with cancer and DVT, and 1030 with SVT but no cancer. Most patients in all subgroups (93%, 99% and 96%, respectively) received anticoagulants, while those with SVT received lower daily doses of low-molecular-weight heparin (114 ± 58, 163 ± 44, and 106 ± 50 IU/kg, respectively). During the first 90 days, 101 patients (3.6%) developed subsequent VTE (PE 47, DVT 41, SVT 13), whereas 72 (2.5%) had major bleeding and 282 (9.9%) died. Among the three groups, 90-day events were, respectively: VTE at rates of 7.3%, 4.0% and 2.4%; major bleeding at rates of 2.7%, 3.9% and 0.3%; mortality at rates of 8.2%, 16% and 0.3%. Between D90 and D180, only one SVT recurrence and one death occurred in SVT cancer patients. In multivariable analysis, cancer was associated with subsequent VTE (HR = 2.04; 1.15-3.62), while initial presentation as SVT or DVT were not associated with a different risk. CONCLUSIONS: The risk for subsequent VTE (including symptomatic SVT, DVT or PE) was similar in cancer patients with isolated SVT than in those with isolated DVT.

Non-compliance with end-of-life parenteral nutrition prescription recommendations: retrospective study of 1,260 cancer patients.

BACKGROUND: Cancer patients near end of life (EOL) often suffer malnourishment and cachexia. In these patients, the prescription of parenteral nutrition (PN) remains highly controversial. Guidelines state that nutritional support does not improve quality of life in dying patients. We aimed to assess the compliance with international recommendations about PN prescription in advanced cancer, identify factors associated with PN at EOL and to evaluate the risk of blood stream infections (BSI). METHODS: Retrospective analysis of data from medical records of patients who died in 2013, 2015, 2017 and 2019 in a cancer center. RESULTS: One thousand two hundred and sixty patients with advanced cancer were included. PN was prescribed in 574 (45.6%) patients, the mean duration of PN was 10±9.7 days. Patients with a severe malnutrition [odds ratio (OR) =2.36; 95% confidence interval (CI): 1.42-4.02], a malignant bowel obstruction (MBO) (OR =2.25; 95% CI: 1.44-3.56), a length of hospitalization >12 days (OR =2.21; 95% CI: 1.67-2.94), a body mass index (BMI) <22.14 kg/m2 (OR =2.02; 95% CI: 1.52-2.67), an antitumor treatment (OR =1.58; 95% CI: 1.14-2.20) were more frequently prescribed a PN. BSI was diagnosed in 113 patients (9%) and was more frequent in patients receiving a PN (13% vs. 6%; OR =2.01; 95% CI: 1.18-3.54). CONCLUSIONS: International guidelines on PN in EOL cancer patients are poorly applied in the studied settings. Factors associated with the use of PN were low BMI, severe malnutrition, antitumor treatment, increased length of hospitalization. These findings argue for the use of a survival estimation tool and a multidisciplinary integrative care intervention when considering PN.

Failure of the Ottawa Score to Predict the Risk of Recurrent Venous Thromboembolism in Cancer Patients: The Prospective PREDICARE Cohort Study.

INTRODUCTION: Recurrent venous thromboembolism (VTE) despite curative anticoagulation is frequent in patients with cancer. Identifying patients with a high risk of recurrence could have therapeutic implications. A prospective study was designed to validate the Ottawa risk score of recurrent VTE in cancer patients. METHODS: In a prospective multicenter observational cohort, adult cancer patients with a recent diagnosis of symptomatic or incidental lower limb deep vein thrombosis or pulmonary embolism (PE) were treated with tinzaparin for 6 months. The primary endpoint was the recurrence of symptomatic or asymptomatic VTE within the first 6 months of treatment. All clinical events were centrally reviewed and adjudicated. Time-to-event outcomes were estimated by the Kalbfleisch and Prentice method to take into account the competing risk of death. A C-statistic value of > 0.70 was needed to validate the Ottawa score. RESULTS: A total of 409 patients were included and analyzed on an intention-to-treat basis. Median age was 68 years, 60.4% of patients had PE, and VTE was symptomatic in 271 patients (66.3%). The main primary sites were lung (31.3%), lower digestive tract (14.4%), and breast (13.9%) cancers. The Ottawa score was high (≥ 1) in 58% of patients. The 6-month cumulative incidence of recurrent VTE was 7.3% (95% confidence interval [CI]: 4.9-11.1) overall, and 5.0% (95% CI: 2.3-10.8) versus 9.1% (95%CI: 6.1-13.6) in the Ottawa low versus high risk groups, respectively. The C-statistic value was 0.60 (95% CI: 0.55-0.65). CONCLUSION: In this prospective cohort of patients with cancer receiving tinzaparin for VTE, the Ottawa score failed to accurately predict recurrent VTE.

Venous thromboembolism associated with central venous catheters in patients with cancer: From pathophysiology to thromboprophylaxis, areas for future studies.

Symptomatic catheter related thrombosis (CRT) occurs in 4%-8% of cancer patients. The mean incidence of CRT, detected either by echography or Doppler ranges between 12 and 14% with a high negative predictive value of about 95%, allowing the subsequent occurrence of CRT (symptomatic and asymptomatic) to be safely excluded. Despite its frequency and its medico-economic consequences, no thromboprophylaxis has been validated to date. In most patients, CRT occurs immediately after catheter insertion, most often within the first week and almost all within the first month after insertion. Meta analyses show a reduction of asymptomatic and symptomatic CRT incidence by about 55%-60% using either vitamin K antagonists or low molecular weight heparins without an increased risk of major bleeding. This pharmacological prophylaxis is only effective when started before the central venous catheter insertion at prophylactic doses and thereafter continued at subtherapeutic doses. Since no population at high risk of CRT has been identified, this review focuses on pathophysiology, epidemiology and clinical supportive data that could lead to a new CRT prophylaxis strategy.

A Pragmatic Study Evaluating NEPA Versus Aprepitant for Prevention of Chemotherapy-Induced Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy.

BACKGROUND: Neurokinin (NK) 1 receptor antagonists (RAs), administered in combination with a 5-hydroxytryptamine-3 (5-HT3 ) RA and dexamethasone (DEX), have demonstrated clear improvements in chemotherapy-induced nausea and vomiting (CINV) prevention over a 5-HT3 RA plus DEX. However, studies comparing the NK1 RAs in the class are lacking. A fixed combination of a highly selective NK1 RA, netupitant, and the 5-HT3 RA, palonosetron (NEPA), simultaneously targets two critical antiemetic pathways, thereby offering a simple convenient antiemetic with long-lasting protection from CINV. This study is the first head-to-head NK1 RA comparative study in patients receiving anthracycline cyclophosphamide (AC) and non-AC moderately emetogenic chemotherapy (MEC). MATERIALS AND METHODS: This was a pragmatic, multicenter, randomized, single-cycle, open-label, prospective study designed to demonstrate noninferiority of single-dose NEPA to a 3-day aprepitant regimen in preventing CINV in chemotherapy-naive patients receiving AC/non-AC MEC in a real-life setting. The primary efficacy endpoint was complete response (no emesis/no rescue) during the overall (0-120 hour) phase. Noninferiority was achieved if the lower limit of the 95% confidence interval (CI) of the difference between NEPA and the aprepitant group was greater than the noninferiority margin set at -10%. RESULTS: Noninferiority of NEPA versus aprepitant was demonstrated (risk difference 9.2%; 95% CI, -2.3% to 20.7%); the overall complete response rate was numerically higher for NEPA (64.9%) than aprepitant (54.1%). Secondary endpoints also revealed numerically higher rates for NEPA than aprepitant. CONCLUSION: This pragmatic study in patients with cancer receiving AC and non-AC MEC revealed that a single dose of oral NEPA plus DEX was at least as effective as a 3-day aprepitant regimen, with indication of a potential efficacy benefit for NEPA. IMPLICATIONS FOR PRACTICE: In the absence of comparative neurokinin 1 (NK1 ) receptor antagonist (RA) studies, guideline committees and clinicians consider NK1 RA agents to be interchangeable and equivalent. This is the first head-to-head study comparing one NK1 RA (oral netupitant/palonosetron [NEPA]) versus another (aprepitant) in patients receiving anthracycline cyclophosphamide (AC) and non-AC moderately emetogenic chemotherapy. Noninferiority of NEPA versus the aprepitant regimen was demonstrated; the overall complete response (no emesis and no rescue use) rate was numerically higher for NEPA (65%) than aprepitant (54%). As a single-dose combination antiemetic, NEPA not only simplifies dosing but may offer a potential efficacy benefit over the current standard-of-care.

Risk of recurrent venous thromboembolism in patients with autoimmune diseases: data from the Registro Informatizado de Enfermedad TromboEmbólica (RIETE) registry.

Autoimmune disease is a risk factor for first incident venous thromboembolism (VTE). However, data on the risk of recurrent VTE in people with autoimmune disease is sparse. We explored the risk of recurrent VTE using the RIETE registry, comparing people with autoimmune disease (n = 1305) to those without (n = 50608). Overall rates were 6.5 and 5.1 recurrent VTE/100 years for patients with autoimmune disease vs controls, respectively. After adjustment for sex and unprovoked/provoked VTE yielded an adjusted hazard ratio of 1.29 (95%CI 1.03-1.62). The analysis was limited by short median follow up time (161 days overall), precluding definitive conclusions on recurrent VTE risks.

[Patients treated with palbociclib and endocrine therapy for metastatic breast cancer: Can we predict the occurrence of severe early hematological toxicity?] / Patients sous palbociclib et hormonothérapie pour un cancer du sein métastatique : peut-on prédire la survenue d'une hématotoxicité précoce et sévère ?

INTRODUCTION: The addition of palbociclib to endocrine therapy has been shown to improve progression free survival in hormone receptor positive metastatic breast cancer patients. This cyclin CDK4/6 inhibitor could expose patients to a grade 3-4 hematological toxicity, leading to treatment discontinuation or treatment interruption that is potentially associated with a lack of efficiency. The aim of this study was to identify predictive factors of severe early hematotoxicity (ESHT). METHODS: This retrospective cohort study included patients who started palbociclib in the Institut Sainte Catherine between December 1, 2016 and January 1, 2019 for the treatment of metastatic breast cancer. Individual data and hematological toxicity were collected from electronic medical records. ESHT was defined as the occurrence, during the first 3 cycles, of grade 4 or grade 3 hematological toxicity requiring palbociclib dose reduction. RESULTS: In total, 181 patients (180 females) were included; median age was 67 years. Forty-six patients (25.4%) experienced an ESHT. Predictive factors of ESHT in multivariate analysis were a performance status (PS) of 2 or more (P=0.024) and an history of radiotherapy of bone metastasis in the previous year (P=0.003). Before palbociclib initiation, a neutrophil count below 3.37g/L was predictive of ESHT with a sensibility of 76% and a specificity of 71%. CONCLUSIONS: ECOG PS, bone radiotherapy within the year and low baseline neutrophils count are associated with ESHT in palbociclib-treated metastatic breast cancer patients. These elements could be useful for a careful monitoring leading to adapted therapy.

Role of supportive care in improving the quality of life and reducing unscheduled hospital care in patients with metastatic breast cancer.

BACKGROUND: Metastatic breast cancer (MBC) patients experience long survival and report poorer quality of life than localized breast cancer patients. Comprehensive supportive care (CSC) has been shown to improve the quality of life (QoL) of MBC. The respective part of each support care has not been fully examined, and little is known about whether meeting patients' needs is accompanied by decreased unscheduled hospital care (UHC). METHODS: This prospective monocentric study included women who started a new treatment line for MBC between January 2018 and December 2018. The endpoints were factors associated with UHC and QoL (SF36) at month 12. RESULTS: 100 patients were offered CSC, 78 were included (21 refusals, 1 no MBC). CSC was provided to 60 patients: pain (43%), psychological (37%), kinesitherapy (30%), social assistance (22%), esthetic (18%), nutrition (18%), massage (13%), and none (10%). CSC rate was not statistically different among patients with (58%) and without UHD (49%). Factors associated with a decrease of UHC were age > 65 years (p = 0.01), no previous treatment for MBC (p = 0.0001) with a trend for the lack of CSC (p = 0.054). Among the 8 domains of the SF36 scale, only health change perception was improved (p = 0.01) and its predictive factors were treatment carried out as planned (p = 0.0004), pain care (p = 0.003), and lack of MBC progression (p = 0.0035). CONCLUSION: CSC can improve QoL in MBC. Painful patients might benefit more from CSC. UHC did not decrease for patients receiving CSC as expected possibly because of their important needs for clinical care.

Identification of factors associated with aggressive end-of-life antitumour treatment: retrospective study of 1282 patients with cancer.

OBJECTIVE: Antitumour treatment in the last 2 weeks of death (ATT-W2) and a new regimen of ATT within 30 days of death (NATT-M1) are considered as aggressive end-of-life (EOL) care. We aimed to assess factors associated with inappropriate use of antitumour treatment (ATT) at EOL. METHODS: Data of patients with cancer who died in 2013, 2015, 2017 and 2019 in a single for-profit cancer centre were retrospectively analysed. ATT was divided into chemotherapy (CT), oral targeted therapy (OTT), hormonotherapy and immunotherapy (IMT). RESULTS: A total of 1282 patients were included. NATT-M1 was given to 197 (15.37%) patients, and 167 (13.03%) had an ATT-W2. Patients with a performance status of <2 and treated with CT had more both ATT- W2 (OR=2.45, 95% CI 1.65 to 3.65, and OR=10.29, 95% CI 4.70 to 22.6, respectively) and NATT-M1 (OR=2.01, 95% CI 1.40 to 2.90, and OR=8.41, 95% CI 4.46 to 15.86). Predictive factors of a higher rate of ATT-W2 were treatment with OTT (OR=19.08, 95% CI 7.12 to 51.07), follow-up by a medical oncologist (OR=1.49, 95% CI 1.03 to 2.17), miscellaneous cancer (OR=3.50, 95% CI 1.13 to 10.85) and length of hospital stay before death of <13 days (OR=1.92, 95% CI 1.32 to 2.79). Urinary tract and male genital cancers received less ATT-W2 (OR=0.38, 95% CI 0.16 to 0.89, and OR=0.40, 95% CI 0.16 to 0.99) and patients treated by IMT or with age <69 years more NATT-M1 (OR=19.21, 95% CI 7.55 to 48.8, and OR=1.69, 95% CI 1.20 to 2.37). Patients followed up by the palliative care team (PCT) had fewer ATT-W2 and NATT-M1 (OR=0.49, 95% CI 0.35 to 0.71, and OR=0.42, 95% CI 0.30 to 0.58). CONCLUSIONS: Most recent ATT and access to a PCT follow-up are the two most important potentially modifiable factors associated with aggressive EOL in patients with cancer. Early integrated palliative oncology care could help to decrease futile ATT at EOL.

[Low-molecular-weight heparins for cancer-associated thromboembolism: What place in 2019?] / Héparines de bas poids moléculaires dans la maladie thromboembolique veineuse liée au cancer : quelle place en 2019 ?

According to international clinical practice guidelines, low-molecular-weight heparins are advocate for the treatment and the prevention of cancer associated thrombosis. Direct oral anticoagulants recently introduced represent an alternative to vitamin K antagonists and low-molecular-weight heparins since their use doesn't require coagulation monitoring or daily subcutaneous injections. Recent studies comparing direct oral anticoagulants and low-molecular-weight heparins have shown a trend towards a reduction of venous thromboembolism events of direct oral anticoagulants but an increased risk of major bleeding. Recent French inter-group recommendations on the treatment of venous thromboembolism in cancer patients, favor low molecular weight heparins over direct oral anticoagulants as curative agents. In the light of recent studies, the objective of this review is to re-evaluate the place of low-molecular-weight heparins in the management of patents with cancer-associated thrombosis and to focus on the recent updates of international guidelines.

Venous Thromboembolism in Patients With Autoimmune Disorders: Findings From the RIETE Registry.

Patients with autoimmune disorders are at an increased risk of venous thromboembolism (VTE), but this association has not been consistently evaluated. We used the RIETE (Registro Informatizado Enfermedad Trombo Embólica) database to compare the rates of VTE recurrences, major bleeding, and death during the course of anticoagulation, according to the presence or absence of autoimmune disorders. Of 71 625 patients with VTE recruited in February 2018, 1800 (2.5%) had autoimmune disorders. Median duration of anticoagulant therapy was slightly longer in patients with autoimmune disorders (median, 190 vs 182 days; P = .001). On multivariable analysis, patients with autoimmune disorders had a similar risk of VTE recurrences (hazard ratio [HR]: 0.93; 95% confidence interval [CI]: 0.68-1.27) or major bleeding (HR: 1.07; 95% CI: 0.82-1.40) and a lower risk to die (HR: 0.66; 95% CI: 0.54-0.81) than those without autoimmune disorders. Patients with giant cell arteritis had the highest rates of major bleeding (8.6 events per 100 patient-years) and the lowest rate of recurrences (zero). In other subgroups, the rates of both events were more balanced. During anticoagulation, patients with or without autoimmune disorders had similar rates of VTE recurrences or major bleeding. However, there were some differences between subgroups of patients with autoimmune disorders.

Impact on health-related quality of life deterioration-free survival of a first-line therapy combining nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil for patients with metastatic pancreatic cancer: Results of the randomized phase II AFUGEM GERCOR clinical trial.

BACKGROUND: The phase II AFUGEM GERCOR trial aimed to assess the efficacy of a first-line therapy combining nab-paclitaxel plus either gemcitabine (gemcitabine group) or simplified leucovorin and fluorouracil (sLV5FU2 group) in patients with previously untreated metastatic pancreatic cancer. Results of progression-free survival at 4 months (primary endpoint) were in favor of the sLV5FU2 group. This paper presents health-related quality of life (HRQoL) data as a secondary endpoint. METHODS: HRQoL was assessed using the EORTC QLQ-C30 questionnaire at baseline and at each chemotherapy cycle until the end of treatment. The HRQoL deterioration-free survival (QFS) was used as a modality of longitudinal analysis. QFS was defined as the time between randomization and the first definitive HRQoL score deterioration as compared to the baseline score, or death. Sensitivity analysis was performed excluding death as an event. Univariate Cox models were used to estimate hazard ratios (HRs) and 90% confidence intervals (CIs) of the treatment effect. RESULTS: Between 2013 and 2014, 114 patients were randomized in a 1:2 ratio (39 in the gemcitabine group and 75 in the sLV5FU2 group). Patients in the sLV5FU2 group seemed to present longer QFS than those of the gemcitabine group for 14 out of 15 dimensions, with HRs < 1. Results of the sensitivity analysis excluding death as an event were significantly in favor of the sLV5FU2 group for physical functioning (HR = 0.51 [90% CI 0.27-0.97]) and pain (HR = 0.26 [90% CI 0.09-0.74]). CONCLUSION: The nab-paclitaxel plus simplified leucovorin and fluorouracil combination had no negative impact in exploratory HRQoL analyses.

[Supportive care for survivors]. / Pour des soins de support de l'après cancer.

Advances in early detection and treatment have pushed in a few decades the management of cancers from a management model of the end of life to the management of a chronic disease. This evolution has accelerated the development of supportive care in two directions, firstly towards the best possible support to the end of life in advanced cancer patients (palliative care) and secondly to the limitation of treatment toxicities, the prevention of relapse and the return to life as "normal" as possible (care for after cancer). If palliative care now has a legitimacy and a solid regulatory base, this is not yet the case of supportive care in France. The content and organization differ depending on the institution, the choice of clinicians and patient preferences. Social networks and media convey messages that blur evidence-based practices. This article aims to review the facilitators and obstacles of this perspective.

Incidence, risk factors, and outcomes of central venous catheter-related thromboembolism in breast cancer patients: the CAVECCAS study.

Previous epidemiologic studies investigating central venous catheter (CVC)-related venous thromboembolism (CRT) were conducted in heterogenous cancer populations and data in breast cancer (BC) remain limited. To investigate the Doppler ultrasound (DUS)-CRT incidence, risk factors and outcomes in BC, we designed a prospective, multicenter cohort of nonmetastatic invasive BC patients undergoing insertion of a CVC for chemotherapy. All patients underwent double-blind DUS before, 7, 30, and 90 days after CVC insertion and a 6 months clinical follow-up. Symptomatic DUS-CRT were treated by anticoagulants. D-Dimers, thrombin generation, and platelet-derived microparticles were measured before and 2 days after CVC placement. In DUS-CRT patients, a nested case-control study analyzed the role of thrombophilia. Among 524 patients, the DUS-CRT (14 symptomatic, 46 asymptomatic) cumulative probability was 9.6% at 3 months and 11.5% at 6 months (overall incidence rate: 2.18/100 patient-months). Ten/14 symptomatic DUS-CRT were detected on double-blind DUS before the clinical symptoms, and 3/14 had a simultaneous pulmonary embolism. No clinical thrombotic event subsequently occurred in untreated asymptomatic DUS-CRT. Age >50 years (OR, 1.80; 95% CI, 1.01-3.22), BMI >30 kg/m² (OR, 2.64; 95% CI, 1.46-4.76) and comorbidities (OR, 2.05; 95% CI, 1.18-3.56) were associated with DUS-CRT. No biomarkers was found to predict DUS-CRT. In multivariate analysis, BMI >30 kg/m² (OR, 2.66; 95%CI, 1.46-4.84) and lobular carcinoma histology (OR, 2.56; 95%CI, 1.32-4.96) remained the only significant DUS-CRT risk factors. Thrombophilia did not account for DUS-CRT. Only clinical parameters identified high risk DUS-CRT patients who may be considered for thromboprophylaxis.

Nab-paclitaxel plus either gemcitabine or simplified leucovorin and fluorouracil as first-line therapy for metastatic pancreatic adenocarcinoma (AFUGEM GERCOR): a non-comparative, multicentre, open-label, randomised phase 2 trial.

BACKGROUND: Nab-paclitaxel plus gemcitabine has become a standard treatment regimen in patients with metastatic pancreatic adenocarcinoma; however, retrospective data suggest that gemcitabine might be inefficient in 50-60% of patients and thus not an optimum regimen in combination with nab-paclitaxel. We did a phase 2 trial to assess the activity and safety of a new regimen of nab-paclitaxel plus simplified leucovorin and fluorouracil. METHODS: We did a non-comparative, multicentre, open-label, randomised phase 2 trial in 15 hospitals and institutions in France. Eligible participants were previously untreated patients with metastatic pancreatic adenocarcinoma (previous adjuvant chemotherapy after curative intent resection was allowed if the interval between the end of chemotherapy and relapse was more than 12 months). Patients had to have at least one measurable lesion assessed by CT scan or MRI and an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. We randomly assigned participants (1:2) centrally to 28-day cycles of either gemcitabine plus nab-paclitaxel or simplified leucovorin and fluorouracil plus nab-paclitaxel. The randomisation was by minimisation, stratified by centre and ECOG performance status. Drugs were administered in each cycle as follows: nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) as 30-min intravenous infusions on days 1, 8, and 15; leucovorin (400 mg/m2) as a 120-min intravenous infusion on days 1 and 15; and fluorouracil (400 mg/m2) as a 5-min bolus intravenous infusion followed by a 46-h continuous intravenous infusion of 2400 mg/m2 on days 1 and 15. Patients continued treatment until unacceptable toxicity, disease progression, or patient withdrawal. The primary endpoint was progression-free survival at 4 months in the first 72 assessable patients in the leucovorin and fluorouracil group, with a target of 50% for the regimen to be deemed sufficiently active to warrant further study. We did the primary analysis on the modified intention-to-treat (ITT) population, defined as all randomly assigned and assessable patients regardless of their eligibility and received treatments. This trial is registered at ClinicalTrials.gov, number NCT01964534. The trial has ended and we report the final analysis here. FINDINGS: Between Dec 12, 2013, and Oct 31, 2014, we randomly assigned 114 patients to treatment: 75 patients to the leucovorin and fluorouracil group and 39 to the gemcitabine group. One patient in the leucovorin and fluorouracil group did not have a 4-month assessment, and was thus excluded from the modified ITT analysis. Median follow-up was 13·1 months (95% CI 12·5-14·1). At 4 months, 40 (56%, 90% CI 45-66) of 72 patients in the leucovorin and fluorouracil group were alive and free from disease progression (21 [54%, 40-68] of 39 patients in the gemcitabine group were also alive and progression-free at 4 months). Grade 3-4 adverse events occurred in 33 (87%) of 38 patients in the gemcitabine group and in 56 (77%) of 73 patients in the leucovorin and fluorouracil group, with different toxicity profiles. The most common grade 3-4 adverse events in the leucovorin and fluorouracil group were neutropenia without fever (17 [23%]), fatigue (16 [22%]), paraesthesia (14 [19%]), diarrhoea (nine [12%]), and mucositis (seven [10%]); in the gemcitabine group they were neutropenia without fever (12 [32%]), thrombocytopenia (seven [18%]), fatigue (eight [21%]), anaemia (five [13%]), increased alanine aminotransferase and aspartate aminotransferase concentrations (five [13%] for both), and paraesthesia (four [11%]). Two participants died; one in the leucovorin and fluorouracil group from septic shock, and one in the gemcitabine group from diabetes compensation with acidosis; these deaths were deemed to be not related to treatment. Treatment-related serious adverse events occurred in 28 (38%) of 73 patients in the leucovorin and fluorouracil group and in 14 (37%) of 38 in the gemcitabine group. INTERPRETATION: Nab-paclitaxel plus simplified leucovorin and fluorouracil fulfilled the primary endpoint in that more than the required 50% of our study population were progression-free at 4 months, with a tolerable toxicity profile. This regimen thus deserves further assessment in a phase 3 trial. FUNDING: GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie) and Celgene through grants to GERCOR.