84 research outputs found

    Surrogate endpoints for early-stage breast cancer: a review of the state of the art, controversies, and future prospects

    Get PDF
    Breast cancer subtypes; Neoadjuvant therapy; Surrogate markersSubtipos de c√°ncer de mama; Terapia neoadyuvante; Marcadores sustitutosSubtipus de c√†ncer de mama; Ter√†pia neoadjuvant; Marcadors substitutsDrug approval for early-stage breast cancer (EBC) has been historically granted in the context of registration trials based on adequate outcomes such as disease-free survival and overall survival. Improvements in long-term outcomes have made it more difficult to demonstrate the clinical benefit of a new cancer drug in large, randomized, comparative clinical trials. Therefore, the use of surrogate endpoints rather than traditional measures allows for cancer drug trials to proceed with smaller sample sizes and shorter follow-up periods, which reduces drug development time. Among surrogate endpoints for breast cancer, the increase in pathological complete response (pCR) rates was considered appropriate for accelerated drug approval. The association between pCR and long-term outcomes was strongest in patients with aggressive tumor subtypes, such as triple-negative and human epidermal growth factor receptor 2 (HER2)-positive/hormone receptor-negative breast cancers. Whereas in hormone receptor-positive/HER2-negative EBC, the most accepted surrogate markers for endocrine therapy‚Äďbased trials include changes in Ki67 and the preoperative endocrine prognostic index. Beyond the classic endpoints, further prognostic tools are required to provide EBC patients with individualized and effective therapies, and the neoadjuvant setting provides an excellent platform for drug development and biomarker discovery. Nowadays, the availability of multigene signatures is offering a standardized quantitative and reproducible tool to potentiate the efficacy of standard treatment for high-risk patients and develop de-escalated treatments for patients at lower risk of relapse. In this article, we first evaluate the surrogacies used for long-term outcomes and the underlying evidence supporting the use of each surrogate endpoint for the accelerated or regular drug approval process in EBC. Next, we provide an overview of the most recent studies and innovative strategies in a (neo)adjuvant setting as a platform to accelerate new drug approval. Finally, we highlight some clinical trials aimed at tailoring systemic treatment of EBC using prognosis-related factors or early biomarkers of drug sensitivity or resistance

    The Impact of Excluding Nonrandomized Studies From Systematic Reviews in Rare Diseases: ‚ÄúThe Example of Meta-Analyses Evaluating the Efficacy and Safety of Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis‚ÄĚ

    Get PDF
    Nonrandomized studies are usually excluded from systematic reviews. This could lead to loss of a considerable amount of information on rare diseases. In this article, we explore the impact of excluding nonrandomized studies on the generalizability of meta-analyses results on mucopolysaccharidosis (MPS) disease. A comprehensive search of systematic reviews on MPS patients up to May 2020 was carried out (CRD42020191217). The primary endpoint was the rate of patients excluded from systematic reviews if only randomized studies were considered. Secondary outcomes included the differences in patient and study characteristics between randomized and nonrandomized studies, the methods used to combine data from studies with different designs, and the number of patients excluded from systematic reviews if case reports were not considered. More than 50% of the patients analyzed have been recruited in nonrandomized studies. Patient characteristics, duration of follow-up, and the clinical outcomes evaluated differ between the randomized and nonrandomized studies. There are feasible strategies to combine the data from different randomized and nonrandomized designs. The analyses suggest the relevance of including case reports in the systematic reviews, since the smaller the number of patients in the reference population, the larger the selection bias associated to excluding case reports. Our results recommend including nonrandomized studies in the systematic reviews of MPS to increase the representativeness of the results and to avoid a selection bias. The recommendations obtained from this study should be considered when conducting systematic reviews on rare diseases

    The role of CDK4/6 inhibitors in early breast cancer

    Get PDF
    The use of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) has proven to be a successful strategy in the treatment of advanced hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer (BC), leading to a strong interest in their possible role in the treatment of early luminal BC. In this review we collect the most relevant and recent information on the use of CDK4/6i for the treatment of early BC in the neoadjuvant and adjuvant settings. Specifically, we evaluate the results of the large phase 3 adjuvant trials recently released, which have yielded apparently divergent results. We also examine the relevance of biomarkers as response predictive factors for CDI4/6i, the combination between radiotherapy and CDK4/6i, and provide a critical discussion on the evidence that we have so far and future directions of the role of these drugs in the treatment of early BC

    The Value of Case Reports in Systematic Reviews from Rare Diseases. The Example of Enzyme Replacement Therapy (ERT) in Patients with Mucopolysaccharidosis Type II (MPS-II)

    Get PDF
    Background: Case reports are usually excluded from systematic reviews. Patients with rare diseases are more dependent on novel individualized strategies than patients with common diseases. We reviewed and summarized the novelties reported by case reports in mucopolysaccharidosis type II (MPS-II) patients treated with enzyme replacement therapy (ERT). Methods: We selected the case reports included in a previous meta-analysis of patients with MPS-II treated with ERT. Later clinical studies evaluating the same topic of those case reports were reported. Our primary aim was to summarize novelties reported in previous case reports. Secondary objectives analyzed the number of novelties evaluated in subsequent clinical studies and the time elapsed between the publication of the case report to the publication of the clinical study. Results: We identified 11 innovative proposals in case reports that had not been previously considered in clinical studies. Only two (18.2%) were analyzed in subsequent nonrandomized cohort studies. The other nine novelties (81.8%) were analyzed in later case reports (five) or were not included in ulterior studies (four) after more than five years from their first publication. Conclusions: Case reports should be included in systematic reviews of rare disease to obtain a comprehensive summary of the state of research and offer valuable information for healthcare practitioners

    The Impact of Excluding Nonrandomized Studies From Systematic Reviews in Rare Diseases: ‚ÄúThe Example of Meta-Analyses Evaluating the Efficacy and Safety of Enzyme Replacement Therapy in Patients With Mucopolysaccharidosis‚ÄĚ

    Get PDF
    Nonrandomized studies are usually excluded from systematic reviews. This could lead to loss of a considerable amount of information on rare diseases. In this article, we explore the impact of excluding nonrandomized studies on the generalizability of meta-analyses results on mucopolysaccharidosis (MPS) disease. A comprehensive search of systematic reviews on MPS patients up to May 2020 was carried out (CRD42020191217). The primary endpoint was the rate of patients excluded from systematic reviews if only randomized studies were considered. Secondary outcomes included the differences in patient and study characteristics between randomized and nonrandomized studies, the methods used to combine data from studies with different designs, and the number of patients excluded from systematic reviews if case reports were not considered. More than 50% of the patients analyzed have been recruited in nonrandomized studies. Patient characteristics, duration of follow-up, and the clinical outcomes evaluated differ between the randomized and nonrandomized studies. There are feasible strategies to combine the data from different randomized and nonrandomized designs. The analyses suggest the relevance of including case reports in the systematic reviews, since the smaller the number of patients in the reference population, the larger the selection bias associated to excluding case reports. Our results recommend including nonrandomized studies in the systematic reviews of MPS to increase the representativeness of the results and to avoid a selection bias. The recommendations obtained from this study should be considered when conducting systematic reviews on rare diseases

    Fulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study

    Get PDF
    PurposeTo compare overall survival (OS) for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer.Patients and MethodsThe Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) was a phase II, randomized, open-label, multicenter trial. Postmenopausal women with estrogen receptor‚Äďpositive, locally advanced/metastatic breast cancer who had no previous therapy for advanced disease received either fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or anastrozole 1 mg (daily). The primary end point (clinical benefit rate [72.5% and 67.0%]) and a follow-up analysis (median time to progression [23.4 months and 13.1 months]) have been reported previously for fulvestrant 500 mg and anastrozole, respectively. Subsequently, the protocol was amended to assess OS by unadjusted log-rank test after approximately 65% of patients had died. Treatment effect on OS across several subgroups was examined. Tolerability was evaluated by adverse event monitoring.ResultsIn total, 205 patients were randomly assigned (fulvestrant 500 mg, n = 102; anastrozole, n = 103). At data cutoff, 61.8% (fulvestrant 500 mg, n = 63) and 71.8% (anastrozole, n = 74) had died. The hazard ratio (95% CI) for OS with fulvestrant 500 mg versus anastrozole was 0.70 (0.50 to 0.98; P = .04; median OS, 54.1 months v 48.4 months). Treatment effects seemed generally consistent across the subgroups analyzed. No new safety issues were observed.ConclusionThere are several limitations of this OS analysis, including that it was not planned in the original protocol but instead was added after time-to-progression results were analyzed, and that not all patients participated in additional OS follow-up. However, the present results suggest fulvestrant 500 mg extends OS versus anastrozole. This finding now awaits prospective confirmation in the larger phase III FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Na√Įve Advanced Breast Cancer) trial (ClinicalTrials.gov identifier: NCT01602380)

    Agreement between results of meta-analyses from case reports and clinical studies, regarding efficacy and safety of idursulfase therapy in patients with mucopolysaccharidosis type II (MPS-II): a new tool for evidence-based medicine in rare diseases

    Get PDF
    Case reports; Clinical studies; Enzyme replacement therapyInformes de casos; Estudios clínicos; Terapia de reemplazo de enzimasInformes de casos; Estudis clínics; Teràpia de reemplaçament enzimàticBackground: A preliminary exploratory study shows solid agreement between the results of case reports and clinical study meta-analyses in mucopolysaccharidosis Type I (MPS-I) adult patients. The aim of the present study is to confirm previous results in another patient population, suffering from mucopolysaccharidosis Type II (MPS-II). Methods: A systematic review and meta-analysis of case reports published by April 2018 was conducted for MPS-II patients treated with enzyme replacement therapy (ERT). The study is reported in accordance with PRISMA and MOOSE guidelines (PROSPERO database code CRD42018093408). The assessed population and outcomes were the same as previously analyzed in a meta-analysis of MPS-II clinical studies. The primary endpoint was the percent of clinical cases showing improvement in efficacy outcome, or no harm in safety outcome after ERT initiation. A restrictive procedure to aggregate case reports, by selecting standardized and well-defined outcomes, was proposed. Different sensitivity analyses were able to evaluate the robustness of results. Results: Every outcome classified as "acceptable evidence group" in our case report meta-analysis had been graded as "moderate strength of evidence" in the aforementioned meta-analysis of clinical studies. Sensitivity, specificity, and positive-negative predictive values for results of both meta-analyses reached 100%, and were deemed equivalent. Conclusions: Aggregating case reports quantitatively, rather than analyzing them qualitatively, may improve conclusions in rare diseases and personalized medicine. Additionally, we propose some methods to evaluate publication bias and heterogeneity of the included studies in a meta-analysis of case reports

    A single-arm study design with non-inferiority and superiority time-to-event endpoints: a tool for proof-of-concept and de-intensification strategies in breast cancer

    Get PDF
    De-escalation trials in oncology evaluate therapies that aim to improve the quality of life of patients with low-risk cancer by avoiding overtreatment. Non-inferiority randomized trials are commonly used to investigate de-intensified regimens with similar efficacy to that of standard regimens but with fewer adverse effects (ESMO evidence tier A). In cases where it is not feasible to recruit the number of patients needed for a randomized trial, single-arm prospective studies with a hypothesis of non-inferiority can be conducted as an alternative. Single-arm studies are also commonly used to evaluate novel treatment strategies (ESMO evidence tier B). A single-arm design that includes both non-inferiority and superiority primary objectives will enable the ranking of clinical activity and other parameters such as safety, pharmacokinetics, and pharmacodynamics data. Here, we describe the statistical principles and procedures to support such a strategy. The non-inferiority margin is calculated using the fixed margin method. Sample size and statistical analyses are based on the maximum likelihood method for exponential distributions. We present example analyses in metastatic and adjuvant settings to illustrate the usefulness of our methodology. We also explain its implementation with nonparametric methods. Single-arm designs with non-inferiority and superiority analyses are optimal for proof-of-concept and de-escalation studies in oncology

    Impact of SARS-CoV-2 Infection on Patients with Cancer: Retrospective and Transversal Studies in Spanish Population

    Full text link
    [EN] Background: Studies of patients with cancer affected by coronavirus disease 2019 (COVID-19) are needed to assess the impact of the disease in this sensitive population, and the influence of different cancer treatments on the COVID-19 infection and seroconversion. Material and Methods: We performed a retrospective analysis of all patients hospitalized with RT-PCR positive for COVID-19 in our region to assess the prevalence of cancer patients and describe their characteristics and evolution (Cohort 1). Concurrently, a transversal study was carried out in patients on active systemic cancer treatment for symptomatology and seroprevalence (IgG/IgM by ELISA-method) against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) (Cohort 2). Results: A total of 215 patients (Cohort 1) were admitted to hospital with a confirmed COVID-19 infection between February 28 and April 30, 2020, and 17 died (7.9%). A medical record of cancer was noted in 43 cases (20%), 6 of them required Intensive care unit ICU attention (14%), and 7 died (16%). There were thirty-six patients (83%) who tested IgG/IgM positive for SARS-CoV-2. Patients on immunosuppressive therapies presented a lower ratio of seroconversion (40% vs. 8%; p = 0.02). In Cohort 2, 166 patients were included in a symptoms-survey and tested for SARS-CoV-2. Any type of potential COVID-19-related symptom was referred up to 67.4% of patients (85.9% vs. 48.2% vs. 73.9%, for patients on chemotherapy, immunotherapy and targeted therapies respectively, p < 0.05). The seroprevalence ratio was 1.8% for the whole cohort with no significant differences by patient or treatment characteristics. Conclusion: Patients with cancer present higher risks for hospital needs for COVID-19 infection. The lack of SARS-CoV-2 seroconversion may be a concern for patients on immunosuppressive therapies. Patients receiving systematic therapies relayed a high rate of potentially COVID-19-related symptoms, particularly those receiving chemotherapy. However, the seroconversion rate remains low and in the range of general population.We thank all the patients who consented to this study, and the frontline healthcare professionals who are involved in patients' care during this pandemic. We also thank the technical assistants: M. Portero Hernandez, A. Real Perez, and M. Ocasar Garcia. VGB's research work is partially supported by the Ministerio de Ciencia e Innovacion of Spain under grant No. PID2019-110442GB-I00.Garde-Noguera, J.; Fern√°ndez-Murga, ML.; Giner-Bosch, V.; Dom√≠nguez-M√°rquez, V.; Garc√≠a S√°nchez, J.; Soler-Catalu√Īa, JJ.; L√≥pez Chuli√°, F.... (2020). Impact of SARS-CoV-2 Infection on Patients with Cancer: Retrospective and Transversal Studies in Spanish Population. Cancers. 12(12):1-11. https://doi.org/10.3390/cancers12123513S1111212Munster, V. J., Koopmans, M., van Doremalen, N., van Riel, D., & de Wit, E. (2020). A Novel Coronavirus Emerging in China ‚ÄĒ Key Questions for Impact Assessment. New England Journal of Medicine, 382(8), 692-694. doi:10.1056/nejmp2000929Coronavirus COVID-19 Global Cases by the Center for Systems Science and Engineeringhttps://coronavirus.jhu.edu/map.htmlInforme Sobre la Situaci√≥n COVID-19 en Espa√Īa a 6 April 2020. Equipo COVID-19. RENAVE. CNE. CNM (ISCIII). Informe COVID-19 n¬ļ21https://covid19.isciii.es/Report 13: Estimating the Number of Infections and the Impact of Non-Pharmaceutical Interventions on COVID-19 in 11 European Countrieshttps://spiral.imperial.ac.uk:8443/handle/10044/1/77731Rothan, H. A., & Byrareddy, S. N. (2020). The epidemiology and pathogenesis of coronavirus disease (COVID-19) outbreak. Journal of Autoimmunity, 109, 102433. doi:10.1016/j.jaut.2020.102433Liang, W., Guan, W., Chen, R., Wang, W., Li, J., Xu, K., ‚Ķ He, J. (2020). Cancer patients in SARS-CoV-2 infection: a nationwide analysis in China. The Lancet Oncology, 21(3), 335-337. doi:10.1016/s1470-2045(20)30096-6Sharpe, A. H., & Pauken, K. E. (2017). The diverse functions of the PD1 inhibitory pathway. Nature Reviews Immunology, 18(3), 153-167. doi:10.1038/nri.2017.108Fisher, R. A. (1922). On the Interpretation of Ōá 2 from Contingency Tables, and the Calculation of P. Journal of the Royal Statistical Society, 85(1), 87. doi:10.2307/2340521Mehta, C. R., & Patel, N. R. (1983). A Network Algorithm for Performing Fisher‚Äôs Exact Test in r √ó c Contingency Tables. Journal of the American Statistical Association, 78(382), 427. doi:10.2307/2288652Wilcoxon, F. (1945). Individual Comparisons by Ranking Methods. Biometrics Bulletin, 1(6), 80. doi:10.2307/3001968Kuderer, N. M., Choueiri, T. K., Shah, D. P., Shyr, Y., Rubinstein, S. M., Rivera, D. R., ‚Ķ de Lima Lopes, G. (2020). Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study. The Lancet, 395(10241), 1907-1918. doi:10.1016/s0140-6736(20)31187-9Zhang, L., Zhu, F., Xie, L., Wang, C., Wang, J., Chen, R., ‚Ķ Zhou, M. (2020). Clinical characteristics of COVID-19-infected cancer patients: a retrospective case study in three hospitals within Wuhan, China. Annals of Oncology, 31(7), 894-901. doi:10.1016/j.annonc.2020.03.296Winter, A. K., & Hegde, S. T. (2020). The important role of serology for COVID-19 control. The Lancet Infectious Diseases, 20(7), 758-759. doi:10.1016/s1473-3099(20)30322-4Venkatesulu, B. P., Thoguluva Chandrasekar, V., Giridhar, P., Advani, P., Sharma, A., Hsieh, C. E., ‚Ķ Krishnan, S. (2020). A systematic review and meta-analysis of cancer patients affected by a novel coronavirus. doi:10.1101/2020.05.27.20115303Van Assen, S., Holvast, A., Benne, C. A., Posthumus, M. D., van Leeuwen, M. A., Voskuyl, A. E., ‚Ķ Bijl, M. (2010). Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab. Arthritis & Rheumatism, 62(1), 75-81. doi:10.1002/art.25033Rousseau, B., Loulergue, P., Mir, O., Krivine, A., Kotti, S., Viel, E., ‚Ķ Tournigand, C. (2012). Immunogenicity and safety of the influenza A H1N1v 2009 vaccine in cancer patients treated with cytotoxic chemotherapy and/or targeted therapy: the VACANCE study. Annals of Oncology, 23(2), 450-457. doi:10.1093/annonc/mdr141Di Cosimo, S., Malfettone, A., P√©rez-Garc√≠a, J. M., Llombart-Cussac, A., Miceli, R., Curigliano, G., & Cort√©s, J. (2020). Immune checkpoint inhibitors: a physiology-driven approach to the treatment of coronavirus disease 2019. European Journal of Cancer, 135, 62-65. doi:10.1016/j.ejca.2020.05.026Bersanelli, M., Scala, S., Affanni, P., Veronesi, L., Colucci, M. E., Banna, G. L., ‚Ķ Liotta, F. (2020). Immunological insights on influenza infection and vaccination during immune checkpoint blockade in cancer patients. Immunotherapy, 12(2), 105-110. doi:10.2217/imt-2019-0200Poll√°n, M., P√©rez-G√≥mez, B., Pastor-Barriuso, R., Oteo, J., Hern√°n, M. A., P√©rez-Olmeda, M., ‚Ķ Fern√°ndez de Larrea, N. (2020). Prevalence of SARS-CoV-2 in Spain (ENE-COVID): a nationwide, population-based seroepidemiological study. The Lancet, 396(10250), 535-544. doi:10.1016/s0140-6736(20)31483-5Choe, P. G., Perera, R. A. P. M., Park, W. B., Song, K.-H., Bang, J. H., Kim, E. S., ‚Ķ Oh, M. (2017). MERS-CoV Antibody Responses 1 Year after Symptom Onset, South Korea, 2015. Emerging Infectious Diseases, 23(7), 1079-1084. doi:10.3201/eid2307.170310Cao, W.-C., Liu, W., Zhang, P.-H., Zhang, F., & Richardus, J. H. (2007). Disappearance of Antibodies to SARS-Associated Coronavirus after Recovery. New England Journal of Medicine, 357(11), 1162-1163. doi:10.1056/nejmc070348Wu, L.-P., Wang, N.-C., Chang, Y.-H., Tian, X.-Y., Na, D.-Y., Zhang, L.-Y., ‚Ķ Liang, G.-D. (2007). Duration of Antibody Responses after Severe Acute Respiratory Syndrome. Emerging Infectious Diseases, 13(10), 1562-1564. doi:10.3201/eid1310.070576Kissler, S. M., Tedijanto, C., Goldstein, E., Grad, Y. H., & Lipsitch, M. (2020). Projecting the transmission dynamics of SARS-CoV-2 through the postpandemic period. Science, 368(6493), 860-868. doi:10.1126/science.abb579

    Japanese subpopulation analysis of MONARCH 2: phase 3 study of abemaciclib plus fulvestrant for treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative breast cancer that progressed on endocrine therapy

    Get PDF
    BACKGROUND: This was a Japanese subpopulation analysis of MONARCH 2, a double-blind, randomized, placebo-controlled, phase 3 study of abemaciclib plus fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer (ABC). METHODS: Eligible women had progressed on (neo)adjuvant endocrine therapy (ET), ‚ÄȂȧ‚ÄČ12¬†months from end of adjuvant ET, or on first-line ET for ABC, and had not received chemotherapy for ABC. Patients were randomized 2:1 to receive abemaciclib or placebo plus fulvestrant. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), pharmacokinetics (PK), health-related quality of life (HRQoL), and safety. RESULTS: In Japan, 95 patients were randomized (abemaciclib, n‚ÄČ=‚ÄČ64; placebo, n‚ÄČ=‚ÄČ31). At final PFS analysis (February 14, 2017), median PFS was 21.2 and 14.3¬†months, respectively, in the abemaciclib and placebo groups (hazard ratio: 0.672; 95% confidence interval: 0.380-1.189). Abemaciclib had a higher objective response rate (37.5%) than placebo (12.9%). PK and safety profiles for Japanese patients were consistent with those of the overall population, without clinically meaningful differences across most HRQoL dimensions evaluated. The most frequent adverse events in the abemaciclib versus placebo groups were diarrhea (95.2 versus 25.8%), neutropenia (79.4 versus 0%), and leukopenia (66.7 versus 0%). At a second data cutoff (June 20, 2019), median OS was not reached with abemaciclib and 47.3¬†months with placebo (hazard ratio: 0.755; 95% confidence interval: 0.390-1.463). CONCLUSIONS: Results of the Japanese subpopulation were consistent with the improved clinical outcomes and manageable safety profile observed in the overall population. CLINICAL TRIAL REGISTRATION: NCT02107703; U.S. National Library of Medicine: https://clinicaltrials.gov/ct2/show/NCT02107703
    • ‚Ķ
    corecore