Evaluating video-based consultations in routine clinical practice at a comprehensive cancer center.

INTRODUCTION: Integrating telemedicine into cancer care remains a major challenge. There are little clinical evidence for teleconsultation efficacy and safety in daily oncology practice. This study as a pioneering experience, aimed to analyze patient and physician opinions regarding the implementation of telemedicine consultations, and to identify major limitations of telehealth spread in an oncology institute. MATERIAL AND METHODS: During COVID-19 lockdown, patients and physicians who took part to at least one video-based teleconsultation between March and May 2020, were enrolled in this observational study. All eligible patients received an anonymous online questionnaire. On the other hand, all physicians eligible to participate were asked through email to complete a questionnaire. RESULTS: In this study, 31 physicians and 304 patients consented to participate in this study by answering the questionnaire and were included. Regarding telemedicine satisfaction, 65.8% of patients were satisfied. The lack of clinical examination was the major limitation reported by 77% of patients. Patients belonging to a high socio-professional category were statistically more dissatisfied with the relationship with their doctor (OR = 2.31 and 95% CI [1.12; 4.74]). CONCLUSION: This study showed promising results of incorporating video-based teleconsultations into cancer patient management. Randomized clinical trials are needed in order to accelerate the digital implementation in clinical practice.

Overall and net survival of patients with sarcoma between 2005 and 2010: Results from the French Network of Cancer Registries (FRANCIM).

BACKGROUND: Sarcomas are rare, heterogeneous, ubiquitously localized malignancies with many histologic subtypes and genomic patterns. The survival of patients with sarcoma has rarely been described based on this heterogeneity; therefore, the authors' objective was to estimate survival outcomes in patients who had sarcomas using the 2020 version of the World Health Organization classification of soft tissue and bone tumors. METHODS: Patients older than 15 years who had incident sarcoma diagnosed between 2005 and 2010 were extracted from 14 French population-based cancer registries covering 18% of the French metropolitan population. Vital status for each patient was actively followed up to June 30, 2013. Net survival (NS) was estimated using the unbiased Pohar-Perme method. RESULTS: Overall, 4202 patients were included. NS declined with increasing age at diagnosis. According to topographic groups, large 5-year NS disparities were observed, ranging from 47% among women with gynecologic sarcomas to 89% among patients with skin sarcomas. Patients with soft tissue, bone, and gastrointestinal sarcomas had 5-year NS rates of 53%, 61%, and 70%, respectively. Similar heterogeneity was observed according to histologic subtypes, with 5-year NS ranging from 19% for patients with angiosarcomas to 96% for patients with dermatofibrosarcomas. Patients with sarcoma who displayed missense mutations had a better 5-year NS (74%); those with MDM2-amplified sarcomas had the worst NS (45%). CONCLUSIONS: NS rates in patients with sarcoma are presented here for the first time based on the 2020 World Health Organization classification applied to population-based registry data. Large prognostic heterogeneity was observed based on age, topographic and histologic groups, and genomic alteration profiles, constituting a benchmark for future studies and clinical trials.

Impact of the COVID-19 lockdown in France on the diagnosis and staging of breast cancers in a tertiary cancer centre.

OBJECTIVES: Due to COVID-19, a lockdown took place between March 17 and May 1, 2020, in France. This study evaluates the impact of the lockdown on the diagnosis and staging of breast cancers in a tertiary cancer centre. METHODS: Our database was searched for all consecutive invasive breast cancers diagnosed in our institution during the lockdown (36 working days), during equivalent periods of 36 working days before and after lockdown and a reference period in 2019. The number and staging of breast cancers diagnosed during and after lockdown were compared to the pre-lockdown and reference periods. Tumour maximum diameters were compared using the Mann-Whitney test. Proportions of tumour size categories (T), ipsilateral axillary lymph node invasion (N) and presence of distant metastasis (M) were compared using Fisher's exact test. RESULTS: Compared to the reference period (n = 40 in average), the number of breast cancers diagnosed during lockdown (n = 32) decreased by 20% but increased by 48% after the lockdown (n = 59). After the lockdown, comparatively to the reference period, breast cancers were more often symptomatic (86% vs 57%; p = 0.001) and demonstrated bigger tumour sizes (p = 0.0008), the rates of small tumours (T1) were reduced by 38%, locally advanced cancers (T3, T4) increased by 80% and lymph node invasion increased by 64%. CONCLUSION: The COVID-19 lockdown was associated with a 20% decrease in the number of diagnosed breast cancers. Because of delayed diagnosis, breast cancers detected after the lockdown had poorer prognosis with bigger tumour sizes and higher rates of node invasion. KEY POINTS: • The number of breast cancer diagnosed in a large tertiary cancer centre in France decreased by 20% during the first COVID-19 lockdown. • Because of delayed diagnosis, breast cancers demonstrated bigger tumour size and more frequent axillary lymph node invasion after the lockdown. • In case of a new lockdown, breast screening programme and follow-up examinations should not be suspended and patients with clinical symptoms should be encouraged to seek attention promptly.

Molecular profiling of advanced soft-tissue sarcomas: the MULTISARC randomized trial.

BACKGROUND: Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant's outcome. METHODS: This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm "NGS" and the standard "No NGS". NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in "No NGS" arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator. DISCUSSION: The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale. TRIAL REGISTRATION: clinicaltrial.gov NCT03784014 .

Determinants of the access to remote specialised services provided by national sarcoma reference centres.

BACKGROUND: Spatial inequalities in cancer management have been evidenced by studies reporting lower quality of care or/and lower survival for patients living in remote or socially deprived areas. NETSARC+ is a national reference network implemented to improve the outcome of sarcoma patients in France since 2010, providing remote access to specialized diagnosis and Multidisciplinary Tumour Board (MTB). The IGéAS research program aims to assess the potential of this innovative organization, with remote management of cancers including rare tumours, to go through geographical barriers usually impeding the optimal management of cancer patients. METHODS: Using the nationwide NETSARC+ databases, the individual, clinical and geographical determinants of the access to sarcoma-specialized diagnosis and MTB were analysed. The IGéAS cohort (n = 20,590) includes all patients living in France with first sarcoma diagnosis between 2011 and 2014. Early access was defined as specialised review performed before 30 days of sampling and as first sarcoma MTB discussion performed before the first surgery. RESULTS: Some clinical populations are at highest risk of initial management without access to sarcoma specialized services, such as patients with non-GIST visceral sarcoma for diagnosis [OR 1.96, 95% CI 1.78 to 2.15] and MTB discussion [OR 3.56, 95% CI 3.16 to 4.01]. Social deprivation of the municipality is not associated with early access on NETSARC+ remote services. The quintile of patients furthest away from reference centres have lower chances of early access to specialized diagnosis [OR 1.18, 95% CI 1.06 to 1.31] and MTB discussion [OR 1.24, 95% CI 1.10 to 1.40] but this influence of the distance is slight in comparison with clinical factors and previous studies on the access to cancer-specialized facilities. CONCLUSIONS: In the context of national organization driven by reference network, distance to reference centres slightly alters the early access to sarcoma specialized services and social deprivation has no impact on it. The reference networks' organization, designed to improve the access to specialized services and the quality of cancer management, can be considered as an interesting device to reduce social and spatial inequalities in cancer management. The potential of this organization must be confirmed by further studies, including survival analysis.

Nurses' internal contamination by antineoplastic drugs in hospital centers: a cross-sectional descriptive study.

OBJECTIVE: The aim of this study was to assess internal antineoplastic drugs (ADs) contamination in the nursing staff in French hospital centers, using highly sensitive analytical methods. METHODS: This cross-sectional study included nurses practicing in care departments where at least one of the five ADs studied was handled (5-fluorouracil, cyclophosphamide, doxorubicin, ifosfamide, methotrexate). The nurses study participation lasted 24 h including collection of three urine samples and one self-questionnaire. All urine samples were assayed by ultra-high-performance liquid chromatography-tandem mass spectrometry methods with very low value of the lower limit of quantification (LLOQ). RESULTS: 74 nurses were included, 222 urine samples and 74 self-questionnaires were collected; 1092 urine assays were performed. The percentage of nurses with internal AD contamination was 60.8% and low levels of urinary concentrations were measured. Regarding nurses with internal contamination (n = 45), 42.2% presented internal contamination by methotrexate, 37.8% by cyclophosphamide, 33.3% by ifosfamide, 17.8% by 5-fluorouracil metabolite and 6.7% by doxorubicine. Among the positive assays, 17.9% (n = 26/145) were not explained by exposure data from the self-questionnaire but this could be due to the skin contact of nurses with contaminated work surfaces. CONCLUSIONS: This study reported high percentage of nurses with internal ADs contamination. The low LLOQ values of the used analytical methods, allowed the detection of ADs that would not have been detected with the current published methods: the percentage of contamination would have been 17.6% instead of the 60.8% reported here. Pending toxicological reference values, urine ADs concentrations should be reduced as low as reasonably achievable (ALARA principle).

Palliative care referral in cancer patients with regard to initial cancer prognosis: a population-based study.

OBJECTIVES: More than half of cancer patients require palliative care; however, inequality in access and late referral in the illness trajectory are major issues. This study assessed the cumulative incidence of first hospital-based palliative care (HPC) referral, as well as the influence of patient-, tumor-, and care-related factors. STUDY DESIGN: This is a retrospective population-based study. METHODS: The study included patients from the 2014 population-based cancer registry of Gironde, France. International Classification of Diseases, Tenth Revision, coding for palliative care identified HPC referrals from 2014 to 2018. The study included 8424 patients. Analyses considered the competing risk of death and were stratified by initial cancer prognosis (favorable vs unfavorable [if metastatic or progressive cancer]). RESULTS: The 4-year incidence of HPC was 16.7% (95% confidence interval, 16.6-16.8). Lung cancer led to more referrals, whereas breast, colorectal, and prostatic locations were associated to less frequent HPC compared with other solid tumors. Favorable prognosis central nervous system tumors and unfavorable prognosis hematological malignancies also showed less HPC. The incidence of HPC was higher in tertiary centers, particularly for older patients. In the favorable prognosis subgroup, older and non-deprived patients received more HPC. In the unfavorable prognosis subgroup, the incidence of HPC was lower in patients who lived in rural areas than those who lived in urban areas. CONCLUSIONS: One-sixth of cancer patients require HPC. Some factors influencing referral depend on the initial cancer prognosis. Our findings support actions to improve accessibility, especially for deprived patients, people living in rural areas, those with hematological malignancies, and those treated outside tertiary centers. In addition, consideration of age as factor of HPC may allow for improved design of the referral system.

Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Patients with Ewing sarcoma or osteosarcoma have a median overall survival of less than 12 months after diagnosis, and a standard treatment strategy has not yet been established. Pharmacological inhibition of MET signalling and aberrant angiogenesis has shown promising results in several preclinical models of Ewing sarcoma and osteosarcoma. We aimed to investigate the activity of cabozantinib, an inhibitor of MET and VEGFR2, in patients with advanced Ewing sarcoma and osteosarcoma. METHODS: We did a multicentre, single-arm, two-stage, phase 2 trial in patients with advanced Ewing sarcoma or osteosarcoma recruited from ten centres in the French Sarcoma Group. Key eligibility criteria were aged 12 years or older, Eastern Cooperative Oncology Group performance status of 0-1, and documented disease progression (according to Response Evaluation Criteria in Solid Tumors version 1.1) before study entry. The number of previous lines of treatment was not limited. Patients received cabozantinib (adults 60 mg, children [<16 years] 40 mg/m2) orally once daily in 28-day cycles until disease progression, unacceptable toxicity, the investigator's decision to discontinue, or participant withdrawal. The primary endpoint for Ewing sarcoma was best objective response within 6 months of treatment onset; for osteosarcoma, a dual primary endpoint of 6-month objective response and 6-month non-progression was assessed. All enrolled patients who received at least one dose of cabozantinib were included in the safety analysis, and all participants who received at least one complete or two incomplete treatment cycles were included in the efficacy population. This study was registered with ClinicalTrials.gov, number NCT02243605. FINDINGS: Between April 16, 2015, and July 12, 2018, 90 patients (45 with Ewing sarcoma 45 with osteosarcoma) were recruited to the study. Median follow-up was 31·3 months (95% CI 12·4-35·4) for patients with Ewing sarcoma and 31·1 months (24·4-31·7) for patients with osteosarcoma. 39 (87%) patients with Ewing sarcoma and 42 (93%) patients with osteosarcoma were assessable for efficacy after histological and radiological review. In patients with Ewing sarcoma, ten (26%; 95% CI 13-42) of 39 patients had an objective response (all partial responses) by 6 months; in patients with osteosarcoma, five (12%; 4-26) of 42 patients had an objective response (all partial responses) and 14 (33%; 20-50) had 6-month non-progression. The most common grade 3 or 4 adverse events were hypophosphataemia (five [11%] for Ewing sarcoma, three [7%] for osteosarcoma), aspartate aminotransferase increase (two [4%] for Ewing sarcoma, three [7%] for osteosarcoma), palmar-plantar syndrome (three [7%] for Ewing sarcoma, two [4%] for osteosarcoma), pneumothorax (one [2%] for Ewing sarcoma, four [9%] for osteosarcoma), and neutropenia (two [4%] for Ewing sarcoma, four [9%] for osteosarcoma). At least one serious adverse event was reported in 61 (68%) of 90 patients. No patients died from drug-related toxic effects. INTERPRETATION: Cabozantinib has antitumor activity in patients with advanced Ewing sarcoma and osteosarcoma and was generally well tolerated. Cabozantinib could represent a new therapeutic option in this setting, and deserves further investigation. FUNDING: Institut Bergonié; French National Cancer Institute; Association pour la Recherche contre le Cancer.

Cytochrome P450 1B1 polymorphism drives cancer cell stemness and patient outcome in head-and-neck carcinoma.

BACKGROUND: Cytochrome P450 1B1 (CYP1B1) is mostly expressed in tumours and displays unusual properties. Its two polymorphic forms were differently associated with anticancer drug sensitivity. We decipher here the role of this polymorphism in anticancer drug efficacy in vitro, in vivo and in the clinical setting. METHODS: From head-and-neck squamous cell carcinoma cell lines not expressing CYP1B1, we generated isogenic derivatives expressing the two forms. Proliferation, invasiveness, stem cell characteristics, sensitivity to anticancer agents and transcriptome were analysed. Tumour growth and chemosensitivity were studied in vivo. A prospective clinical trial on 121 patients with advanced head-and-neck cancers was conducted, and a validation-retrospective study was conducted. RESULTS: Cell lines expressing the variant form displayed high rates of in vitro proliferation and invasiveness, stemness features and resistance to DNA-damaging agents. In vivo, tumours expressing the variant CYP1B1 had higher growth rates and were markedly drug-resistant. In the clinical study, overall survival was significantly associated with the genotypes, wild-type patients presenting a longer median survival (13.5 months) than the variant patients (6.3 months) (p = 0.0166). CONCLUSIONS: This frequent CYP1B1 polymorphism is crucial for cancer cell proliferation, migration, resistance to chemotherapy and stemness properties, and strongly influences head-and-neck cancer patients' survival.

Predictive factors of 5-year relapse-free survival in HR+/HER2- breast cancer patients treated with neoadjuvant endocrine therapy: pooled analysis of two phase 2 trials.

BACKGROUND: Few data are available on survival and predictive factors in early breast cancer (BC) patients treated with neoadjuvant endocrine therapy (NET). METHODS: This is a pooled analysis of two multicentre, randomised non-comparative phase 2 clinical trials evaluating neoadjuvant anastrozole and fulvestrant efficacy for postmenopausal HR+/HER2- breast cancer patients: HORGEN (NCT00871858) and CARMINA02 (NCT00629616) studies. RESULTS: In total, 236 patients were included in CARMINA02 and HORGEN trials. Modified intention-to-treat analysis was available for 217 patients. Median follow-up was 65.2 months. Relapse-free survival (RFS) and overall survival (OS) at 5 years were 83.7% (95% CI: 77.9-88) and 92.7% (95% CI: 88.2-95.6), respectively, with no difference between treatment arms. On univariate analysis, tumour staging (T2 vs T3-4; p = 0.0001), Ki-67 at surgery (≤10% vs >10%; p = 0.0093), pathological tumour size (pT1-2 vs pT3-4; p = 0.0012) and node status (pN negative vs positive; p = 0.007), adjuvant chemotherapy (p = 0.0167) and PEPI score (PEPI group I + II vs III; p = 0.0004) were associated with RFS. No events were observed in patients with pathological response according to the Sataloff classification. Multivariate analysis showed that preoperative endocrine prognostic index (PEPI) group III was associated with significantly worse RFS (p = 0.0069, hazard ratio = 3.33 (95% CI: 1.39-7.98)). CONCLUSIONS: Postmenopausal HR+/HER2- breast cancer patients receiving NET generally have a favourable outcome. The PEPI score identifies a subset of patients of poorer prognosis who are candidates for further additional treatment.

Incidence and time trends of sarcoma (2000-2013): results from the French network of cancer registries (FRANCIM).

BACKGROUND: The exhaustive collection of new sarcoma cases and their second histologic review offer a unique opportunity to study their incidence and time trends in France according to the major subtypes. METHODS: Data were collected from population-based cancer registries covering 22% of the French population. Crude and world age-standardized incidence rates (ASR) were estimated according to anatomic, histological and genetic groups, age and sex over the 2010-2013 period. RESULTS: Time trends in incidence were calculated by the annual percent change over the 2000-2013 period. During the most recent period (2010-2013), 3942 patients with sarcoma were included. The ASR of soft-tissue and bone sarcomas, and gastro-intestinal stromal tumors (GIST) were 2.1, 1.0 and 0.6, respectively. For the four most frequent histological subtypes (unclassified, leiomyosarcoma, GIST and liposarcoma), the ASR ranged from 0.4 to 0.7. ASRs were 1.9 for complex genomic and 1.3 for recurrent translocation sarcomas. The time-trend analysis showed a significant increase of sarcoma incidence rate between 2000 and 2005, which stabilized thereafter. Incidence rates increased for four histological subtypes (GIST, chondrosarcoma, myxofibrosarcoma, solitary fibrous tumors) and decreased for three (leiomyosarcomas, Kaposi sarcoma and fibrosarcoma). CONCLUSION: To our knowledge, this study is the first to investigate sarcoma incidence based on a systematic pathological review of these cancers and on the updated sarcoma classifications. Due to the paucity of literature on sarcomas, future studies using data from population-based cancer registries should consider a standardized inclusion criterion presented in our study to better describe and compare data between countries.

[Clinical trials and elderly patients with cancer, the Geriatric Core Dataset (G-Code) tool]. / Essais cliniques et personnes âgées cancéreuses, l'outil Geriatric Core Dataset (G-Code).

Faced with the lack of evidence-based medicine concerning the efficacy and tolerance of cancer treatments in the extremely heterogeneous elderly population, and with no standardised geriatric evaluation in geriatric oncology clinical trials, the intergroup Dialog set itself the objective of establishing a minimal standardised geriatric evaluation for clinical trials. The evaluation must be simple, short and effective. It must comprise validated and reproducible measurement tools. The Geriatric Core Dataset, made up of seven items, has been formalised and validated by national and international experts.

HPV and cofactors for invasive cervical cancer in Morocco: a multicentre case-control study.

BACKGROUND: Limited national information is available in Morocco on the prevalence and distribution of HPV-sub-types of cervical cancer and the role of other risk factors. The aim was to determine the frequency of HPV-sub-types of cervical cancer in Morocco and investigate risk factors for this disease. METHODS: Between November 2009 and April 2012 a multicentre case-control study was carried out. A total of 144 cases of cervical cancer and 288 age-matched controls were included. Odds-ratios and corresponding confidence-intervals were computed by conditional logistic regression models. RESULTS: Current HPV infection was detected in 92.5% of cases and 13.9% of controls. HPV16 was the most common type for both cases and controls. Very strong associations between HPV-sub-types and cervical cancer were observed: total-HPV (OR = 39), HPV16 (OR = 49), HPV18 (OR = 31), and multiple infections (OR = 13). Education, high parity, sexual intercourse during menstruation, history of sexually transmitted infections, and husband's multiple sexual partners were also significantly associated with cervical cancer in the multivariate analysis. CONCLUSIONS: Our results could be used to establish a primary prevention program and to prioritize limited screening to women who have specific characteristics that may put them at an increased risk of cervical cancer.

Optimizing the G8 Screening Tool for Older Patients With Cancer: Diagnostic Performance and Validation of a Six-Item Version.

BACKGROUND: A multidimensional geriatric assessment (GA) is recommended in older cancer patients to inventory health problems and tailor treatment decisions accordingly but requires considerable time and human resources. The G8 is among the most sensitive screening tools for selecting patients warranting a full GA but has limited specificity. We sought to develop and validate an optimized version of the G8. PATIENTS AND METHODS: We used a prospective cohort of cancer patients aged ≥ 70 years referred to geriatricians for GA (2007-2012: n = 729 [training set]; 2012-2014: n = 414 [validation set]). Abnormal GA was defined as at least one impaired domain across seven validated tests. Multiple correspondence analysis, multivariate logistic regression, and bootstrapped internal validation were performed sequentially. RESULTS: The final model included six independent predictors for abnormal GA: weight loss, cognition/mood, performance status, self-rated health status, polypharmacy (≥ 6 medications per day), and history of heart failure/coronary heart disease. For the original G8, sensitivity was 87.2% (95% confidence interval, 84.3-89.7), specificity 57.7% (47.3-67.7), and area under the receiver-operating characteristic curve (AUROC) 86.5% (83.5-89.6). The modified G8 had corresponding values of 89.2% (86.5-91.5), 79.0% (69.4-86.6), and 91.6% (89.3; 93.9), with higher AUROC values for all tumor sites and stable properties on the validation set. CONCLUSION: A modified G8 screening tool exhibited better diagnostic performance with greater uniformity across cancer sites and required only six items. If these features are confirmed in other settings, the modified tool may facilitate selection for a full GA in older patients with cancer. IMPLICATIONS FOR PRACTICE: Several screening tools have been developed to identify older patients with cancer likely to benefit from a complete geriatric assessment, but none combines appropriate sensitivity and specificity. Based on a large prospective cohort study, an optimized G8 tool was developed, combining a systematic statistical approach with expert judgment to ensure optimal discriminative power and clinical relevance. The improved screening tool achieves high sensitivity, high specificity, better homogeneity across cancer types, and greater parsimony with only six items needed, facilitating selection for a full geriatric assessment.

Role of geriatric intervention in the treatment of older patients with cancer: rationale and design of a phase III multicenter trial.

BACKGROUND: In the general geriatric population, programs linking geriatric evaluation with interventions are effective for improving functional status and survival of the patients. Whether or not these interventions improve health related quality of life (HRQoL) or overall survival (OS) in older patients with cancer is not yet clear. Indeed, randomized data on the effect of such interventions on survival and HRQoL are rare and conflicting. We describe the rationale and design of a phase III multicenter trial aimed at assessing the efficacy of geriatric intervention in the management of elderly patients with cancer. METHODS/DESIGN: Approximately 1200 patients, 70 years and older, considered in need of a geriatric intervention based on the G8 screening tool will be randomized into two intervention arms. The 'Usual-care' arm involves standard oncological care based on pre-defined oncological protocols. In addition to the standard oncological care, the 'Case-management' arm involves a multidimensional geriatric assessment and interventions tailored for the patient. Efficacy will be assessed using a co-primary endpoint encompassing OS and HRQoL. DISCUSSION: This trial has been designed to assess whether focused geriatric case management can either improve OS or HRQoL in elderly cancer patients considered in need of geriatric assessment. TRIAL REGISTRATION: Clinicaltrials.gov ID: NCT02704832 .

PRognostic factor of Early Death In phase II Trials or the end of 'sufficient life expectancy' as an inclusion criterion? (PREDIT model).

BACKGROUND: Optimizing patient selection is a necessary step to design better clinical trials. 'Life expectancy' is a frequent inclusion criterion in phase II trial protocols, a measure that is subjective and often difficult to estimate. The aim of this study was to identify factors associated with early death in patients included in phase II studies. METHODS: We retrospectively collected medical records of patients with advanced solid tumors included in phase II trials in two French Comprehensive Cancer Centers (Bordeaux, Center 1 set; Lille, Center 2 set). We analyzed patients' baseline characteristics. Predictive factors associated with early death (mortality at 3 months) were identified by logistic regression. We built a model (PREDIT, PRognostic factor of Early Death In phase II Trials) based on prognostic factors isolated from the final multivariate model. RESULTS: Center 1 and 2 sets included 303 and 227 patients, respectively. Patients from Center 1 and 2 sets differed in tumor site, urological (26 % vs 15 %) and gastrointestinal (18 % vs 28 %) and in lung metastasis incidence (10 % vs 49 %). Overall survival (OS) at 3 months was 88 % (95 % CI [83.5; 91.0], Center 1 set) and 91 % (95 % CI [86.7; 94.2], Center 2 set). Presence of a 'life expectancy' inclusion criterion did not improve the 3-month OS (HR 0.6, 95 % CI [0.2; 1.2], p = 0.2325). Independent factors of early death were an ECOG score of 2 (OR 13.3, 95%CI [4.1; 43.4]), hyperleukocytosis (OR 5.5, 95 % CI [1.9; 16.3]) and anemia (OR 2.8, 95 % CI [1.1; 7.1]). Same predictive factors but with different association levels were found in the Center 2 set. Using the Center 1 set, ROC analysis shows a good discrimination to predict early death (AUC: 0.89 at 3 months and 0.86 at 6 months). CONCLUSIONS: Risk modeling in two independent cancer populations based on simple clinical parameters showed that baseline ECOG of 2, hyperleukocytosis and anemia are strong early-death predictive factors. This model allows identifying patients who may not benefit from a phase II trial investigational drug and may, therefore, represent a helpful tool to select patients for phase II trial entry.

Time-varying coefficients in a multivariate frailty model: Application to breast cancer recurrences of several types and death.

During their follow-up, patients with cancer can experience several types of recurrent events and can also die. Over the last decades, several joint models have been proposed to deal with recurrent events with dependent terminal event. Most of them require the proportional hazard assumption. In the case of long follow-up, this assumption could be violated. We propose a joint frailty model for two types of recurrent events and a dependent terminal event to account for potential dependencies between events with potentially time-varying coefficients. For that, regression splines are used to model the time-varying coefficients. Baseline hazard functions (BHF) are estimated with piecewise constant functions or with cubic M-Splines functions. The maximum likelihood estimation method provides parameter estimates. Likelihood ratio tests are performed to test the time dependency and the statistical association of the covariates. This model was driven by breast cancer data where the maximum follow-up was close to 20 years.

The Role of Sentinel Lymph Node Biopsy and Factors Associated with Invasion in Extensive DCIS of the Breast Treated by Mastectomy: The Cinnamome Prospective Multicenter Study.

BACKGROUND: When invasive components are discovered at mastectomy for vacuum-assisted biopsy (VAB)-diagnosed ductal carcinoma in situ (DCIS), the only option available is axillary lymph node dissection (ALND). The primary aim of this prospective multicenter trial was to determine the benefit of performing upfront sentinel lymph node (SLN) biopsy for these patients. The secondary aim was to determine DCIS factors associated with microinvasion or invasion. METHODS: The SLN procedure was performed during mastectomy, and for positive SLN an ALND was performed during the same intervention. A tissue microarray containing DCIS lesions from the mastectomy specimens was subsequently performed. RESULTS: From May 2008 to December 2010, 228 patients were enrolled from 14 French cancer centers, including 192 eligible patients with pure DCIS on VAB and successful SLN procedures. ALND was avoided for 51 [67 %; 95 % confidence interval (CI), 56-77 %] of all the patients who had microinvasive DCIS or DCIS associated with invasive carcinoma at mastectomy and a negative SLN. Of the 192 patients, 76 (39 %) with VAB-diagnosed DCIS were upgraded after mastectomy to micro (n = 20) or invasive disease (n = 56). The rate of positive SLN for patients with DCIS on VAB was 14 %. High nuclear grade of DCIS was associated with greater risk of microinvasion and invasion, and HER2-amplified DCIS was associated with greater risk of invasion. CONCLUSIONS: Underestimation of invasive components is high when DCIS is diagnosed by VAB in patients undergoing mastectomy. Upfront SLN for patients with VAB-diagnosed extensive DCIS avoids unnecessary ALND for two-thirds of patients with micro or invasive disease on mastectomy.

Validation of death prediction after breast cancer relapses using joint models.

BACKGROUND: Cancer relapses may be useful to predict the risk of death. To take into account relapse information, the Landmark approach is popular. As an alternative, we propose the joint frailty model for a recurrent event and a terminal event to derive dynamic predictions of the risk of death. METHODS: The proposed prediction settings can account for relapse history or not. In this work, predictions developed on a French hospital series of patients with breast cancer are externally validated on UK and Netherlands registry data. The performances in terms of prediction error and calibration are compared to those from a Landmark Cox model. RESULTS: The error of prediction was reduced when relapse information was taken into account. The prediction was well-calibrated, although it was developed and validated on very different populations. Joint modelling and Landmark approaches had similar performances. CONCLUSIONS: When predicting the risk of death, accounting for relapses led to better prediction performance. Joint modelling appeared to be suitable for such prediction. Performance was similar to the landmark Cox model, while directly quantifying the correlation between relapses and death.

Mobile phone use and brain tumours in the CERENAT case-control study.

UNLABELLED: The carcinogenic effect of radiofrequency electromagnetic fields in humans remains controversial. However, it has been suggested that they could be involved in the aetiology of some types of brain tumours. OBJECTIVES: The objective was to analyse the association between mobile phone exposure and primary central nervous system tumours (gliomas and meningiomas) in adults. METHODS: CERENAT is a multicenter case-control study carried out in four areas in France in 2004-2006. Data about mobile phone use were collected through a detailed questionnaire delivered in a face-to-face manner. Conditional logistic regression for matched sets was used to estimate adjusted ORs and 95% CIs. RESULTS: A total of 253 gliomas, 194 meningiomas and 892 matched controls selected from the local electoral rolls were analysed. No association with brain tumours was observed when comparing regular mobile phone users with non-users (OR=1.24; 95% CI 0.86 to 1.77 for gliomas, OR=0.90; 95% CI 0.61 to 1.34 for meningiomas). However, the positive association was statistically significant in the heaviest users when considering life-long cumulative duration (≥896 h, OR=2.89; 95% CI 1.41 to 5.93 for gliomas; OR=2.57; 95% CI 1.02 to 6.44 for meningiomas) and number of calls for gliomas (≥18,360 calls, OR=2.10, 95% CI 1.03 to 4.31). Risks were higher for gliomas, temporal tumours, occupational and urban mobile phone use. CONCLUSIONS: These additional data support previous findings concerning a possible association between heavy mobile phone use and brain tumours.