[Actuality of conflicts of interests in medicine. From financial interests to the run for scientific publication]. / Actualité des conflits d'intérêts en médecine. Des intérêts financiers à la course à la publication scientifique.

Clinical practice and medical research can expose to several situations with risks of conflicts of interests. Such situations can induce attenuations of their primary professional interest in favor of, so-called, secondary interests, and leading to bias in their judgement and actions. In this area, if financial conflicts of interests are consistent and frequently dominant, intellectual conflicts of interests have to be analyzed and considered, like those amplified and even induced by the current tremendous competition for scientific publication. In this article, after a contextual review of conflicts of interests in medicine, we will document and discuss more specifically those frequently induced by leaks of financial interests and those linked by evolutions of the current scientific expansion and competition.

The use of 'added benefit' to determine the price of new anti-cancer drugs in France, 2004-2017.

BACKGROUND: Increasing drug prices strains budgets. Assessing the relation between added benefit and prices can help clinical decision-making and resource allocation. METHODS: We assessed, over a period of 13 years, the relation between added therapeutic benefit and prices for drugs to treat solid tumours in France using the French High Authority of Health Scale (ASMR) and the European Society for Medical Oncology-Magnitude of Clinical Benefit Scale (MCBS). RESULTS: In total, 36 medications were approved for 68 indications. There was a weak correlation between ASMR and MCBS scales (Spearman's |ρ| = 0.28). Drugs had low added benefit on both ASMR (71%) and MCBS (49%). Mean monthly price for new drugs was €4616 (S.D., €3096), ranging from €1795 to €19,675 and increased by 47% comparing 2004-2012 with 2013-2017. The mean monthly price difference of new drugs over their comparator was €3700 (S.D., €3934) ranging between a €13,853 decrease and a €19,675 increase. There was a weak but statistically significant correlation between ASMR and price (|ρ| = 0.35, p = 0.004) and between MCBS and price (|ρ| = 0.33, p = 0.005). Correlations between added benefit and prices were similar or higher for first indications (ASMR, |ρ| = 0.37, p = 0.030; MCBS, |ρ| = 0.48, p = 0.004). In first indications, mean monthly prices increased €3954 for drugs without ASMR added benefit. The mean annual price and price increase for first indications offering no ASMR benefit was €57,312 and €47,448, respectively. CONCLUSION: Prices and benefit are weakly correlated. However, prices increased substantially even for drugs with no added benefit.

[E-health and "Cancer outside the hospital walls", Big Data and artificial intelligence]. / Santé numérique et « cancer hors les murs ¼, Big Data et intelligence artificielle.

To heal otherwise in oncology has become an imperative of Public Health and an economic imperative in France. Patients can therefore receive live most of their care outside of hospital with more ambulatory care. This ambulatory shift will benefit from the digital revolution and the development of digital health or e-health. Cancer research will also benefit with Big Data and artificial intelligence, which gather and analyze a huge amount of data. In this synthesis, we describe the different e-health tools and their potential impacts in oncology, at the levels of education and information of patients and caregivers, prevention, screening and diagnosis, treatment, follow-up, and research. A few randomized studies have already demonstrated clinical benefits. Large Big Data projects such as ConSoRe and Health Data Hub have been launched in France. We also discuss the issues and limitations of "cancer outside the hospital walls and e-health" from the point of view of patients, health care professionals, health facilities and government. This new organization will have to provide remote support "outside the walls" with care and follow-up of quality, continuous and prolonged in total safety and equity. Ongoing and future randomized clinical trials will need to definitively demonstrate areas of interest, advantages and drawbacks not only for patients, but also for caregivers, health facilities and governments.

Outpatient Cancer Care Delivery in the Context of E-Oncology: A French Perspective on "Cancer outside the Hospital Walls".

In oncology, the treatment of patients outside of hospitals has become imperative due to an increasing number of patients who are older and live longer, along with issues such as medical desertification, oncologist hyperspecialization, and difficulties in financing mounting health expenditures. Treatments have become less "invasive", with greater precision and efficiency. Patients can therefore receive most of their care outside of hospitals. The development of e-health can address these new imperatives. In this letter, we describe the different e-health tools and their potential clinical impacts in oncology, as already reported at every level of care, including education, prevention, diagnosis, treatment, and monitoring. A few randomized studies have yet demonstrated the clinical benefit. We also comment on issues and limits of "cancer outside the hospital walls" from the point of view of patients, health care professionals, health facilities, and public authorities. Care providers in hospitals and communities will have to adapt to these changes within well-coordinated networks in order to better meet patient expectations regarding increasing education and personalizing management. Ultimately, controlled studies should aim to definitively demonstrate areas of interest, benefits, and incentives, for not only patients, but also caregivers (formal and informal) and health care providers, health care facilities, and the nation.

[Cancer medicines: reasons for anger]. / Médicaments du cancer : les raisons de la colère.

Cancer medicines: reasons for anger. The recent emergence of innovative therapeutics in oncology parallels growing concerns about their soaring prices. In the USA, this rapid inflation has already resulted in major inequalities in the access to cancer care and in the development of the so-called "financial toxicity", whereas in France it could dangerously threaten the social insurance system. According to the pharmaceutical industries, high prices are primarily justified by major investments in research and development but recent paradigmatic changes in this sector (rationalization of target identification, frequently originating from academic research teams, accelerated or conditional registration procedures, precision medicine with molecular-driven rather than histology-based indication, and large dissemination of immunotherapies) are challenging such a perspective. In this context, physicians, civil society and patients are increasingly supporting transparency in a fair process of drug pricing.

Médicaments du cancer : les raisons de la colère. L'émergence récente de thérapeutiques innovantes en cancérologie s'accompagne d'une inquiétude croissante concernant l'augmentation parallèle de leur prix. Cette inflation rapide, déjà à l'origine, aux États-Unis, d'inégalités patentes dans l'accès aux soins et du phénomène de toxicité financière des anticancéreux, pourrait à brève échéance augmenter de façon dangereuse les contraintes financières pesant sur notre système d'assurance sociale. Alors que les prix élevés sont présentés par l'industrie comme inéluctablement rattachés aux coûts majeurs en recherche et développement, les changements de paradigmes récents dans ce domaine (identification rationalisée et souvent académique des cibles d'intérêt, procédures d'enregistrement accéléré ou conditionnel, indication trans-organes favorisée par la médecine de précision, et développement très large des approches d'immunothérapie) remettent en cause ces arguments. Dans ce contexte, les médecins comme la société civile et les patients réclament que soit défini de façon transparente un juste prix de ces innovations thérapeutiques.

[Anticancer drugs: Which prices for therapeutic innovations?]. / Médicaments du cancer : quelles innovations et à quel prix ?

The expanding knowledge of the biological mechanisms underlying tumor development made it possible the recent emergence of new therapeutic approaches that are considered as undoubtedly innovative. Yet, to define and to evaluate the magnitude of a drug innovation require an examination of its intrinsic drug properties, medical utility as well as its mode of emergence. Recently, international academic societies, such as ESMO and ASCO, have proposed practical tools that may help quantifying the medical value of a given innovation. Currently, the sustained flux of therapeutic innovations in oncology is associated with an unprecedented growth of costs, the actual determinants of which remain under debate, but raising the critical issue of drugs pricing, and their potential individual or societal "financial toxicity".

Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia.

IL-2 is a natural, T cell-derived cytokine that stimulates the cytotoxic functions of T and natural killer cells. IL-2 monotherapy has been evaluated in several randomized clinical trials (RCTs) for remission maintenance in patients with acute myeloid leukemia (AML) in first complete remission (CR1), and none demonstrated a significant benefit of IL-2 monotherapy. The objective of this meta-analysis was to reliably determine IL-2 efficacy by combining all available individual patient data (IPD) from 5 RCTs (N = 905) and summary data from a sixth RCT (N = 550). Hazard ratios (HRs) were estimated using Cox regression models stratified by trial, with HR < 1 indicating treatment benefit. Combined IPD showed no benefit of IL-2 over no treatment in terms of leukemia-free survival (HR = 0.97; P = .74) or overall survival (HR = 1.08; P = .39). Analyses including the sixth RCT yielded qualitatively identical results (leukemia-free survival HR = 0.96, P = .52; overall survival HR = 1.06; P = .46). No significant heterogeneity was found between the trials. Prespecified subset analyses showed no interaction between the lack of IL-2 effect and any factor, including age, sex, baseline performance status, karyotype, AML subtype, and time from achievement of CR1 to initiation of maintenance therapy. We conclude that IL-2 alone is not an effective remission maintenance therapy for AML patients in CR1.

Gene expression profile predicts outcome after anthracycline-based adjuvant chemotherapy in early breast cancer.

Prognosis of early beast cancer is heterogeneous. Today, no histoclinical or biological factor predictive for clinical outcome after adjuvant anthracycline-based chemotherapy (CT) has been validated and introduced in routine use. Using DNA microarrays, we searched for a gene expression signature associated with metastatic relapse after adjuvant anthracycline-based CT without taxane. We profiled a multicentric series of 595 breast cancers including 498 treated with such adjuvant CT. The identification of the prognostic signature was done using a metagene-based supervised approach in a learning set of 323 patients. The signature was then tested on an independent validation set comprising 175 similarly treated patients, 128 of them from the PACS01 prospective clinical trial. We identified a 3-metagene predictor of metastatic relapse in the learning set, and confirmed its independent prognostic impact in the validation set. In multivariate analysis, the predictor outperformed the individual current prognostic factors, as well as the Nottingham Prognostic Index-based classifier, both in the learning and the validation sets, and added independent prognostic information. Among the patients treated with adjuvant anthracycline-based CT, with a median follow-up of 68 months, the 5-year metastasis-free survival was 82% in the "good-prognosis" group and 56% in the "poor-prognosis" group. Our predictor refines the prediction of metastasis-free survival after adjuvant anthracycline-based CT and might help tailoring adjuvant CT regimens.

How different are luminal A and basal breast cancers?

Heterogeneity of breast cancer makes its evolution difficult to predict, and its treatment far from being optimal. At least 5 main molecular subtypes exist. Two major subtypes are luminal A and basal subtypes, which have opposite features, notably survival. To characterize these 2 subtypes better, with the hope of better understanding their different biology and clinical outcome, we have profiled a series of 138 tumours (80 luminal A and 58 basal) using Affymetrix whole-genome DNA microarrays. We have identified 5,621 probe sets as differentially expressed between the 2 subtypes in our series. These differences were validated in 6 independent public series (more than 600 tumours) profiled using different DNA microarrays platforms. Analysis of functions and pathways related to these probe sets, and the extent of the observed differences, confirmed that the 2 subtypes represent very distinct entities. Genes associated with proliferation, cell cycle, cell motility, angiogenesis, and NFkB signalling were overexpressed in basal tumours. Genes involved in fatty acid metabolism, TGFB signalling, and oestrogen receptor (ER) signalling were overexpressed in luminal A samples. Half of the genes overexpressed in luminal tumours contained ER-binding sites. The number of differentially expressed genes was as high as the set of genes discriminating 2 cancers of different anatomical origin (breast and colon) or discriminating acute myeloid and lymphoid leukaemia. We provide a comprehensive list of genes/pathways that define potential diagnostic, prognostic and therapeutic targets for these 2 subtypes, which should be treated differently given the profound differences observed at the molecular level.

Phase III double-blind, placebo-controlled study of thalidomide in extensive-disease small-cell lung cancer after response to chemotherapy: an intergroup study FNCLCC cleo04 IFCT 00-01.

PURPOSE: This randomized, double-blind, placebo-controlled phase III study aimed to determine whether thalidomide prolongs survival of patients with extensive-disease small-cell lung cancer (SCLC). PATIENTS AND METHODS: One hundred nineteen patients received two courses of etoposide, cisplatin, cyclophosphamide, and 4'-epidoxorubicin (PCDE). Responder patients who had recovered from chemotherapy toxicity were randomly assigned to receive four additional PCDE cycles plus thalidomide (400 mg daily) or placebo. RESULTS: After the first two PCDE cycles, objective response rate was 81.5%, and 92 patients were randomly assigned to placebo (n = 43) or thalidomide (n = 49). Median exposure duration to placebo was 4.5 months, and median exposure to thalidomide was 4.9 months. Patients treated with thalidomide had a longer survival compared with patients who received placebo, although the difference was not statistically significant (minimal follow-up, 3 years; median survival time, 11.7 v 8.7 months, respectively; log-rank test: hazard ratio [HR] = 0.74; 95% CI, 0.49 to 1.12; P = .16). Patients with a performance status (PS) of 1 or 2 who received thalidomide had a significantly longer survival (HR = 0.59; 95% CI, 0.37 to 0.92; P = .02). The disease also progressed slower in patients with PS of 1 or 2 receiving thalidomide (HR = 0.54; 95% CI, 0.36 to 0.87; P = .02), whereas the difference did not reach statistical significance for the whole population (HR = 0.74; 95% CI, 0.49 to 1.12; P = .15). Neuropathy occurred more frequently in the thalidomide group compared with the placebo group (33% v 12%, respectively). CONCLUSION: Treatment with thalidomide was not associated with a significant improvement in survival of SCLC patients. There was pronounced heterogeneity in survival outcomes between groups of patients. Some benefit was observed among patients with a PS of 1 or 2 (exploratory analyses), deserving further studies targeting angiogenesis in this disease.

Lung cancer in elderly patients: a retrospective analysis of practice in a single institution.

UNLABELLED: Incidence of non-small cell lung cancer is increasing especially among elderly with about 40% arising in patients over 70 years old. Most of these elderly patients are under treated. Seventy-one patients with lung cancer over 70 years old were treated in Institut Paoli-Calmettes from January 2000 until December 2003 (male/female: 57/14). Median age was 75.5 years (70-92). OMS 0-1-2-3=4.2-60.6-25.4-4.2%, respectively. Comorbidities were represented by arterial hypertension, coronaropathy, cardiac failure, thrombo-embolism, respiratory failure, diabetes, vascular cerebral dysfunction, and renal failure. 29.6% of patients were without comorbidity, and 14.1% had at least three comorbidities. The averages of the Charlson comorbidity score and the Age-Charlson comorbidity score were 3.4 and 6.6, respectively. Histological characteristics: epidermoïd/adenocarcinoma/undifferentiated/small cells: 39.4%/26.8%/15.5%/9.9%. Most of them were advanced lung cancer: St IIIB=14 (19.7%) and St IV=37 (52.1%). Forty-six patients received chemotherapy (64.8%) with 40 patients (86.9%) with platin (carboplatin or cisplatin). The median number of treatment cycles was 4.1 (range 1-7). Two patients achieved complete response and 15 had partial response. The response rate was 39.6%. The 1-year survival rate was 48.5% and the estimated median survival time was 11 months (95%; 7-18 months) for all patients. The 1-year survival rate was 75% and 21.6% and the estimated median survival time was 25.9 months (95%; 12.6, ND) and 5.7 months (95%; 4.2-9.6) for stage IIIB and IV, respectively. Toxicities were judged acceptable with 19 hospitalizations after chemotherapy, for 16 patients who represent 34.8% of patients who received chemotherapy. CONCLUSIONS: Chemotherapy is feasible in elderly patients with lung cancer. Patients should be evaluated for chemotherapy based on their performance status and comorbidities especially with geriatric assessment rather than age alone. The chemotherapy with platinum seems to be tolerable and effective.

Assessment of care by breast cancer patients participating or not participating in a randomized controlled trial: a report with the Patients' Committee for Clinical Trials of the Ligue Nationale Contre le Cancer.

PURPOSE: Cancer patients participating in randomized controlled trials (RCTs) have not been found to have better clinical outcomes than other patients. Our objective was to assess the impact of RCTs on patients' satisfaction with care. PATIENTS AND METHODS: A prospective study was carried out in a cohort of women with breast cancer (N = 455) divided into those invited to participate in an RCT (201 acceptances, 66 refusals) and a comparable control group not invited to participate (n = 188). All the patients underwent the same treatment (fluorouracil, epirubicin, and cyclophosphamide 100 mg/m2 for six cycles). One and 7 months after the beginning of chemotherapy, self-administered satisfaction scores were used to compare the women's assessment of their care (Comprehensive Assessment of Satisfaction with Care validated scale). RESULTS: At the beginning of chemotherapy, women to whom RCT had been proposed rated the doctors' availability (average +/- standard deviation [SD]: RCT acceptance group, 3.60 +/- 0.78; RCT refusal group, 3.68 +/- 0.87; control group, 3.41 +/- 0.82; P < or = .02) and the doctors' communication (average +/- SD: RCT acceptance group, 3.56 +/- 0.88; RCT refusal group, 3.67 +/- 0.88; control group, 3.39 +/- 0.84; P .05) higher than those to whom the trial was not proposed. After the treatment, participants in the RCT felt that their doctor was more supportive (average +/- SD: RCT acceptance group, 3.04 +/- 0.92; control group, 2.77 +/- 0.85; P = .005) and more informative about their illness and treatment (average +/- SD: RCT acceptance group, 3.34 +/- 0.88; control group, 3.08 +/- 0.92; P = .006) than those in the control group. The general level of satisfaction was also higher in the RCT acceptance group. CONCLUSION: Women participating in an RCT have a more positive picture of their doctors' care than others, probably because of the structural effects of the informed consent and data collection processes.

Comorbidity is an independent predictor of complete remission in elderly patients receiving induction chemotherapy for acute myeloid leukemia.

BACKGROUND: : Elderly patients with acute myeloid leukemia (AML) have a poor prognosis, which is explained by the disease itself and by host-related factors. The objective of this study was to determine the prognostic role of comorbidities in this population. METHODS: : For this single-center, retrospective study, the authors analyzed the outcome of 133 patients aged >/=70 years who received induction chemotherapy for nonpromyelocytic AML between 1995 and 2004. Comorbidities were evaluated by using an adapted form of the Charlson comorbidity index (CCI). RESULTS: : The median patient age was 73 years. The CCI score was 0 for 83 patients (68%), 1 for 16 patients (13%), and >1 for 23 patients (19%). The complete remission (CR) rate was 56%, and the median overall survival was 9 months. In multivariate analysis, 4 adverse prognostic factors for CR were identified: unfavorable karyotype, leukocytosis >/=30 g/L, CD34 expression on leukemic cells, and CCI >1. A score could be generated to allow the stratification of patients into low-, intermediate-, and high-risk groups with CR rates of 87%, 63%, and 37%, respectively. The risk of early mortality and the probability of survival also were different in the 3 risk groups (P = .02 and P = .01, respectively). CONCLUSIONS: : The results from this study indicated that associated comorbidities are independent factors that may influence achievement of CR in elderly patients with AML. Such a scoring system may be useful in the prognostic staging systems that are used to identify patients with AML who can benefit from induction chemotherapy.