Clinical benefit of anti-PD-(L)1 immunotherapies in advanced cancer in France: a population-based estimate from 2014 to 2021.

BACKGROUND: In France, the potential benefit of new treatments is initially evaluated by the Haute Autorité de Santé to determine reimbursement and pricing, but rarely afterwards. Although immunotherapies (ITs) have considerably improved the survival of patients, few data are available on their long-term benefit at a population-treated level. The present retrospective study aimed to assess the clinical benefit of ITs compared to the previous standards of care (SoCs) in France from 2014 to 2021. MATERIALS AND METHODS: To do this, we analyzed all ITs from the anti-programmed cell death protein 1/programmed death-ligand 1 [anti-PD-(L)1] class used in monotherapy or in association with another treatment available in early access or reimbursed in France between 2014 and 2021, regardless of indication. The number of patients initiating an IT was retrieved by year, drug and indication. Using extrapolated Kaplan-Meier curves, utility scores and the population treated, the clinical benefit was expressed as the number of deaths prevented (DP), life-years (LYs) and quality-adjusted life years (QALYs) gained compared to previous SoC. RESULTS: Across the period, five ITs were marketed in 21 indications related to eight primary tumor sites. Between 2014 and 2021, 132 924 patients initiated an IT. By December 2021, 16 173 (13 804-17 141) deaths were delayed compared to previous SoC, mainly in lung cancer. Compared to their SoC, ITs provided a gain of 37 316 (33 581-41 048) additional LYs and 27 709 (23 784-30 450) additional QALYs. Lung cancer was the driver indication with 70.6% of LYs and 68.4% of QALYs gained followed by melanoma with 18.7% and 20.4% of the gain, respectively. CONCLUSIONS: Significant gains in DP, LYs and QALYs have been observed in France following the introduction of ITs.

Time to next treatment or death as a candidate surrogate endpoint for overall survival in advanced melanoma patients treated with immune checkpoint inhibitors: an insight from the phase III CheckMate 067 trial.

BACKGROUND: Time to next treatment or death (TNT-D) may be a patient-relevant endpoint in patients treated with immune checkpoint inhibitors. This study investigated TNT-D as a surrogate endpoint (SE) for overall survival (OS) in previously untreated advanced melanoma patients. METHODS: Patient-level data from the 60-month results of the CheckMate 067 randomised, controlled trial were used. Analyses were carried out for nivolumab monotherapy or nivolumab with ipilimumab versus ipilimumab monotherapy. The SE 1-step validation method based on a joint frailty-copula model was used where the country of enrolment was applied to define clusters. Kendall's τ and the coefficient of determination (R2trial) were estimated for respective measurements of association at the individual and cluster levels. The surrogate threshold effect, the maximum threshold hazard ratio for TNT-D that would translate into OS benefit, was estimated. A leave-one-out cross-validation analysis was carried out to evaluate model robustness. RESULTS: Fifteen clusters of data were generated from 945 patients. For both nivolumab-containing arms, the association between TNT-D and OS was deemed acceptable at the individual level (Kendall's τ > 0.60) and strong at the cluster level, with R2trial fairly close to 1, with narrow confidence intervals. The estimated surrogate threshold effects were 0.61 for nivolumab versus ipilimumab and 0.49 for nivolimub + ipilimumab versus ipilimumab. Cross-validation results showed minimum variation of the correlation measures and satisfactory predictive accuracy for the model. CONCLUSION: Results suggest that TNT-D may be a valuable SE in previously untreated advanced melanoma patients treated with immune checkpoint inhibitors. Surrogacy analyses considering multiple randomised controlled trials are warranted for confirming these findings.

Management of lung cancer patients' quality of life in clinical practice: a Delphi study.

BACKGROUND: The assessment of health-related quality of life (HRQoL) has seen exponential growth in oncology clinical trials. However, the measurement of HRQoL has yet to be optimised in routine clinical practice. This study aimed at exploring the operationalisation of HRQoL in clinical practice with the goal of reaching a consensus from a panel of physicians. MATERIALS AND METHODS: Physicians involved in the management of lung cancer patients in France were recruited to participate in a Delphi study. The study involved three rounds of iterated queries to gain consensus on management aspects of HRQoL, including timing of discussion on HRQoL, which specific domains of HRQoL should be discussed, and what was the most appropriate method of assessment. The threshold adopted for consensus was at least 70% agreement among physicians. A scientific committee reviewed results following each round of the Delphi study. RESULTS: A representative panel of 60 physicians participated in this study. Consensus was obtained for HRQoL management at all time points in the patient care pathway. Panellists agreed that HRQoL discussions should occur during routine visits and hospitalisation. The involvement of patients' relatives was also recognised as important, except when discussing side-effects and involvement of a multidisciplinary team. There was a lack of consensus on a systematic assessment for all patients at each visit and no consensus on how HRQoL should be measured in clinical practice. CONCLUSIONS: HRQoL discussions are considered an integral part in the management of lung cancer patients, and are deemed key to success in patient-physician interaction. Further research is required to harmonise how best to implement HRQoL assessment.

Stroke prevention in patients with atrial fibrillation in France: comparative cost-effectiveness of new oral anticoagulants (apixaban, dabigatran, and rivaroxaban), warfarin, and aspirin.

OBJECTIVES: To conduct an economic evaluation of the currently prescribed treatments for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) including warfarin, aspirin, and novel oral anticoagulants (NOACs) from a French payer perspective. METHODS: A previously published Markov model was adapted in accordance to the new French guidelines of the Commission for Economic Evaluation and Public Health (CEESP), to adopt the recommended efficiency frontier approach. A cohort of patients with NVAF eligible for stroke preventive treatment was simulated over lifetime. Clinical events modeled included strokes, systemic embolism, intracranial hemorrhage, other major bleeds, clinically relevant non-major bleeds, and myocardial infarction. Efficacy and bleeding data for warfarin, apixaban, and aspirin were obtained from ARISTOTLE and AVERROES trials, whilst efficacy data for other NOACs were from published indirect comparisons. Acute medical costs were obtained from a dedicated analysis of the French national hospitalization database (PMSI). Long-term medical costs and utility data were derived from the literature. Univariate and probabilistic sensitivity analyses were performed to assess the robustness of the model projections. RESULTS: Warfarin and apixaban were the two optimal treatment choices, as the other five treatment strategies including aspirin, dabigatran 110 mg, dabigatran in sequential dosages, dabigatran 150 mg, and rivaroxaban were strictly dominated on the efficiency frontier. Further, apixaban was a cost-effective alternative vs warfarin with an incremental cost of €2314 and an incremental quality-adjusted life year (QALY) of 0.189, corresponding to an incremental cost-effectiveness ratio (ICER) of €12,227/QALY. CONCLUSIONS: Apixaban may be the most economically efficient alternative to warfarin in NVAF patients eligible for stroke prevention in France. All other strategies were dominated, yielding apixaban as a less costly yet more effective treatment alternative. As formally requested by the CEESP, these results need to be verified in a French clinical setting using stroke reduction and bleeding safety observed in real-life patient cohorts using these anticoagulants.

Validation of the adherence evaluation of osteoporosis treatment (ADEOS) questionnaire for osteoporotic post-menopausal women.

SUMMARY: We developed and validated a specific 12-item questionnaire to evaluate adherence to oral antiresorptive medication by post-menopausal osteoporotic women in everyday practice. Over the following 9 months, an index of ≤16 was associated with an increase in the risk of treatment discontinuation of 1.69 and of 2.10 for new patients who had started treatment within the previous year. INTRODUCTION: Adherence to medication in osteoporosis is poor. The goal of this study was to develop and validate a disease-specific questionnaire to evaluate adherence to treatment of women with post-menopausal osteoporosis taking oral antiresorptive medication. METHODS: A prototype adherence questionnaire with 45 items developed from patient interview, literature review, and physician opinion was evaluated in a sample of 350 post-menopausal women with osteoporosis treated in primary care. Item responses were matched against scores on the Morisky Medication Adherence Scale (MMAS). The most discriminant items were retained in the final questionnaire. Concurrent and predictive validity were assessed. RESULTS: Twelve items were associated with MMAS score at a probability level of 0.05. These were retained in the final questionnaire which provided an adherence index ranging from 0 to 22. An index of ≥20 was associated with a high probability of persistence and an index ≤ 16 with a high probability of treatment discontinuation in the following 9 months. CONCLUSIONS: The ADEOS-12 is a simple patient-reported measure to determine adherence to osteoporosis treatments with good concurrent and discriminant validity. This is the first disease-specific adherence measure to have been developed for osteoporosis.

Adherence to monthly and weekly oral bisphosphonates in women with osteoporosis.

UNLABELLED: This primary care database survey evaluated whether osteoporotic women treated with bisphosphonates were more adherent to monthly than to weekly treatment. Both compliance (medication possession ratio [MPR]) and persistence (time to discontinuation) were superior in the monthly ibandronate treatment group. Better control of fracture risk may thus be achieved using monthly treatment regimens. INTRODUCTION: Treatment adherence in osteoporosis is poor. The objective of this study was to evaluate whether monthly bisphosphonate treatment provided superior adherence than weekly treatment. METHODS: We analysed medical claims from a national prescription database (Thales). All women aged >45 years receiving a first prescription of monthly ibandronate or weekly bisphosphonates in 2007 were included. Treatment adherence was monitored from initial prescription until January 2008. Compliance was measured by the MPR and persistence by the time from treatment initiation to discontinuation. Multivariate analysis was used to identify variables independently associated with adherence. RESULTS: Twelve-month persistence rates were 47.5% for monthly ibandronate and 30.4% for weekly bisphosphonates. Compliance was significantly higher in the monthly cohort (MPR = 84.5%) than in the weekly cohort (MPR = 79.4%). After adjustment for potential confounding variables, women with monthly regimens were 37% less likely to be non-persistent (HR = 0.63 [0.56-0.72]) and presented a 5% higher mean MPR (84.5% versus 79.3%, p < 0.001) than women with weekly regimens. Other major factors associated with improved adherence were previous densitometry and calcium or vitamin D supplementation (p < 0.01). CONCLUSIONS: Adherence to bisphosphonates may be superior for monthly treatment than for weekly treatment and may thus provide improved fracture protection.

[Management of patients with benign prostatic hyperplasia by urologists: the DUO study]. / Prise en charge, par les urologues, des patients présentant une hypertrophie bénigne de prostate: l'etude DUO.

UNLABELLED: The DUO study intended to define the factors determining diagnostic and treatment strategies for benign prostatic hyperplasia (BPH) management. METHODS: This longitudinal, observational study was conducted in France (June 2004 to March 2005), with a representative sample of private and hospital urologists. RESULTS: 1027 BPH patients were included by 202 urologists and 856 were followed-up 6 months later. Mean I-PSS was 14.9 (+/- 6.7) at inclusion and 10.5 (+/- 6.7) at the follow up visit. At inclusion, pharmacologic treatment was prescribed to 84% of the patients, surgery to 13% and no treatment to 3%. Factors in favour of surgery (versus drugs) were BPH severity (OR = 2.5 if IPSS = 20), patients' choice (OR = 2.5), quality of life improvement (OR = 2.2), post-void residual (OR = 2.1) and dribbling (OR = 1.6). Patients' age and prostatic volume have no impact on this choice. Factors in favour of a combination of an alpha-blocker plus an 5alpha-reductase inhibitor (versus an alpha-blocker) were prostate volume (OR = 7.8), patient's age (OR-3.0 if age = 74) and post-void residual (OR = 2.3) and those in favour of a 5alpha reductase inhibitor (versus an alpha-blocker) were prostate volume (OR = 7.6), PSA results (OR = 5.8), patients' age (OR = 5.4 if > 74 years, OR = 2.1 if > 68 years). CONCLUSION: Medical or surgical treatment of BPH results in IPSS improvement at 6 months. Patients' age and prostatic volume favour 5alpha-reductase inhibitor initiation and have no impact on surgical treatment decision. Surgery is performed in severe BPH or when patients expecting a quality of life improvement do that choice.

[Prevalence and comorbidity of psychiatric disorders in the French general population]. / Prévalence et comorbidité des troubles psychiatriques dans la population générale française: résultats de l'étude épidémiologique ESEMeD/MHEDEA 2000/ (ESEMeD).

INTRODUCTION: ESEMeD is the first international epidemiological study using a random sampling method that has allowed the prevalence of psychiatric disorders in France to be measured with precision and compared directly with that observed in other European countries. OBJECTIVES: 1) To determine the 12 month and lifetime prevalence of mood -disorders, anxiety disorders and alcohol-related disorders. 2) To estimate the comorbidity between these disorders. 3) To evaluate potential demographic risk factors for these disorders. METHODS: This was a transversal survey carried out between 2001 and 2003 of non-institutionalised subjects aged 18 or over in the general population of Germany (n = 3,555), Belgium (n = 2,419), Spain (n = 5,473), France (n = 2,894), the Netherlands (n = 2,372) and Italy (n = 4,712). In France, the sampling source was a randomly generated list of telephone numbers. Subjects were interviewed at home by professional interviewers. The WMH-CIDI questionnaire was used. RESULTS: The participation rate was 46% for France and 61% for all six countries combined. The 12 month and lifetime prevalence rates observed were respectively 6.0% and 21,4% for major depressive episodes, 1.6% and 7.9% for dysthymia, 2.1% and 6.0% for the generalised -anxiety disorders, 1.2% and 3.0% for panic disorders, 0.6% and 1.8% for agoraphobia, 2.2% and 3.9% for post-traumatic stress disorder, 1.7% and 4.7% for social phobia, 4.7% and 11,6% for specific phobia, 0.5% and 4.1% for alcohol abuse and 0.3% and 1.6% for alcohol dependence. Mood disorders and anxiety disorders were significantly more frequent in women, whilst alcohol-related disorders were more frequent in men. The prevalence of all three types of disorder was lower in elderly subjects and in those living in a rural environment. Mood disorders and alcohol-related disorders were more frequent in individuals living alone and mood disorders more frequent in those without paid employment. 38% of subjects with mood disorder also presented an anxiety disorder or an alcohol-related disorder. The comorbidity of mood and anxiety disorders was more frequent in women, younger subjects and those living alone. The comorbidity rate in subjects with anxiety disorders was 26% and did not differ between genders. For alcohol-related disorders, there was a striking difference in comorbidity rate between men and women: 26% in the former and 67% in the latter. CONCLUSION: This study underlines the high prevalence of mood disorders, anxiety disorders and alcohol-related disorders in France and demonstrates a high degree of comorbidity between them. For this reason, it is important to evaluate and take into account potential comorbidity in the management of individuals with psychiatric disorders.

The burden cost of French patients suffering from irritable bowel syndrome.

BACKGROUND: The impact of irritable bowel syndrome (IBS) on health-care resource use in France is evaluated, and explanatory variables determined. METHODS: A questionnaire comprising socio-demographic characteristics, symptoms, consumption of resources, quality of life and impact of IBS on productivity was administered by telephone to a sample of 253 French adults with IBS recruited from the general population, and diagnosed with IBS using several well-known diagnostic criteria. The medical costs were estimated on a monthly basis and included medication(s), physicians' consultations, investigations and hospitalizations. RESULTS: Mean age was 48.3 years and 75% of subjects were women (192). Thirty-six percent of subjects had suffered from IBS for more than 10 years; 77% had consulted a general practitioner and 43% a gastroenterologist. Twenty-nine percent of subjects had undergone an investigation and 25% reported hospitalization; 61% of patients reported that they were taking medication. The average monthly medical costs was 71.8 euros (95% CI = [57.6-86.0]) with an asymmetric distribution (median = 28.1 euros) because of a high proportion of subjects (27%) who reported receiving no care at all. The two principal cost components were investigations (39%), and hospitalizations (22%). The highest medical costs were associated with subjects who were very elderly or suffered from severe symptoms (very severe pain), and were correlated with the lowest quality of life scores. CONCLUSION: IBS has a major impact on resource consumption and the productivity of patients. Determination of the variables to explain medical costs showed that advanced age, severe pain and deterioration in quality of life could be predictive of high medical costs.

Use and misuse of triptans in France: data from the GRIM2000 population survey.

The extent and nature of triptan use for headache relief has been evaluated in a large epidemiological survey in the French general population. Over 25 000 individuals were screened for headache and for triptan use. Of this sample, 290 triptan users were identified from whom extensive data on headache characteristics and healthcare resource consumption were obtained. The use of triptans is relatively infrequent, 0.2% in the general population, with only 7.5% of migraine sufferers using these drugs. The majority of triptan users were female (80%) and presented headache characteristics typical of migraine (80%). The remaining 20% of subjects were thus using triptans for headache types in which the utility of these drugs has not been demonstrated. Among migraineurs, triptan consumers reported more frequent and severe headaches than non-consumers, and reported a higher incidence of nausea and vomiting. The principal determinant of triptan prescription was consultation with a general practitioner (GP), which may itself have been triggered by the severity of the headaches. GPs, rather than specialists, are the primary prescribers of triptans in France.

Estimating the cost-effectiveness of stroke units in France compared with conventional care.

BACKGROUND AND PURPOSE: The incidence of stroke in France is estimated at between 120 000 and 150 000 cases per year. This modeling study assessed the clinical and economic benefits of establishing specialized stroke units compared with conventional care. METHODS: Data from the Dijon stroke registry were used to determine healthcare trajectories according to the degree of autonomy and organization of patient care. The relative risks of death or institutionalization or death or dependence after passage through a stroke unit were compared with conventional care. These risks were then inserted with the costing data into a Markov model to estimate the cost-effectiveness of stroke units. RESULTS: Patients cared for in a stroke unit survive more trimesters without sequelae in the 5 years after hospitalization than those cared for conventionally (11.6 versus 8.28 trimesters). The mean cost per patient at 5 years was estimated at 30 983 for conventional care and 34 638 in a stroke unit. An incremental cost-effectiveness ratio for stroke units of 1359 per year of life gained without disability was estimated. CONCLUSIONS: The cost-effectiveness ratio for stroke units is much lower than the threshold (53 400 ) of acceptability recognized by the international scientific community. This finding justifies organizational changes in the management of stroke patients and the establishment of stroke units in France.

Prevalence and clinical characteristics of migraine in France.

OBJECTIVE: To determine the prevalence and clinical features of migraine and related headache types in France. METHODS: The authors recruited a population of subjects with headache representative of the national population using a stratified sampling method. They screened 10,585 subjects aged 15 and older who were representative of the general population. They identified 1,486 of these as having headaches, and these subjects were subsequently interviewed for information on clinical features, natural history, and functional impact of headache. The authors categorized subjects based on the International Headache Society (IHS) classification and assessed disability using the MIDAS questionnaire. RESULTS: The authors found a standardized prevalence for migraine (IHS categories 1.1 and 1.2) of 7.9% (11.2% for women and 4.0% for men) and 9.1% for migrainous disorder (IHS category 1.7). Migraine attacks were associated with a considerable degree of handicap in activities of daily living, with a MIDAS grade distribution of 74.7% (grade 1), 13.3% (grade 2), 7.7% (grade 3), and 4.3% (grade 4). The prevalence of migraine with MIDAS grade 3 or 4 was 1.6%. CONCLUSIONS: The prevalence of migraine (IHS categories 1.1 and 1.2) in France is 7.9%, and that of total migraine is 17.0%; this does not seem to have evolved over the past 10 years.

[Prevalence of lower urinary tract disorders and incontinence in Auxerre. French segment of the UrEpik study]. / Prévalence des troubles du bas appareil urinaire et de l'incontinence chez les adultes auxerrois. Volet français de l'étude UrEpik.

OBJECTIVES: To estimate the prevalence of low urinary tract symptoms (LUTS) and urinary incontinence among men and women aged 40 to 79 years. METHODS: A postal survey was carried out in a community-dwelling random sample, in Auxerre, France. LUTS were assessed using the International Prostate Symptom Score (IPSS). Urinary incontinence (UI) was assessed using a score based upon four questions. RESULTS: 1216 men and 591 women participated in the survey. 19.2% of men and 13.7% of women reported moderate to severe LUTS (IPSS > 7). 73% of men and 29% of women suffered from UI. Among men and women reporting severe symptoms of UI (0.4 and 5.4% respectively), one third had been prescribed medications for urinary disorders within the previous six months. CONCLUSION: This survey confirms the high prevalence of LUTS and urinary incontinence among a community-dwelling sample of men and women, and highlights the need for management of these disorders.

[Prevalence of nocturia among people in Auxerre: the French part of the UrEpik study]. / Prévalence de la nycturie chez les adultes auxerrois: volet français de l'étude UrEpik.

OBJECTIVES: To estimate the prevalence of nocturia among men and women aged 40 to 79 years old. MATERIAL AND METHODS: A postal survey was carried out in a community-dwelling random sample in Auxerre, France. Nocturia was assessed using the item 7 of the International Prostate Symptom Score (IPSS). RESULTS: 1216 men and 591 women participated in the survey. Average nocturnal urinary frequency was 0.98 and 0.95 among men and women, respectively. Between the age ranges 40-49 years and 70-79 years, the frequency increased from 0.70 to 1.61 among men, and from 0.72 to 1.31 among women. In the age range 70-79 years, 48.1% of men and 31% of women awakened from sleep to urinate at least twice per night. CONCLUSION: Patients and primary care physicians should be more informed about screening and management options, and impact of nocturia on quality of life and related morbidity.