Publications by authors named "Francis A Lévi"

14 Publications

  • Page 1 of 1

Timing of blood sampling to alleviate chemotherapy contraindications.

Support Care Cancer 2021 May 10. Epub 2021 May 10.

Cancer Chronotherapy Team, Cancer Research Centre, Division of Biomedical Sciences, Warwick Medical School, Coventry, UK.

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http://dx.doi.org/10.1007/s00520-021-06256-zDOI Listing
May 2021

Impact of assessment frequency of patient-reported outcomes: an observational study using an eHealth platform in cancer patients.

Support Care Cancer 2021 May 8. Epub 2021 May 8.

Warwick Medical School & Cancer Research Centre, University of Warwick, Coventry, UK.

Background And Aim: The evaluation of patient-reported outcomes (PRO) in cancer has proven relevant positive clinical impact on patients' communication with healthcare professionals, decision-making for management, well-being, and overall survival. However, the optimal frequency of PRO assessment has yet to be defined. Based on the assumption that more frequent sampling would enhance accuracy, we aimed at identifying the optimal sampling frequency that does not miss clinically relevant insight.

Methods: We used pilot data from 31 advanced cancer patients who completed once daily the 19-item MD Anderson Symptom Inventory at home. The resulting dataset allowed us to compare different PRO assessment frequencies to daily sampling, i.e., alternate days (q2d), every third day (q3d), or once a week (q1w). We evaluated the sampling frequencies for two main outcomes: average symptom intensity and identification of severe symptoms.

Results: The majority of the differences between corresponding averages of daily data and those for q2d, q3d, and q1w datasets were close to 0, yet the extremes exceeded 5. Clinically meaningful differences, i.e., > 1, were observed in 0.76% of patient items for q2d, in 2.72% for q3d, and in 11.93% for q1w. Moreover, median values of missed instances of a severe symptom (i.e., > 6) were 14.6% for q2d, 27.8% for q3d, and 55.6% for q1w.

Conclusions: Our analysis suggests that in patients receiving chemotherapy for advanced cancer, increasing the density of PRO collection enhances the accuracy of PRO assessment to a clinically meaningful extent. This is valid for both computations of averages symptom burden and for the recognition of episodes of severe symptom intensity.
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http://dx.doi.org/10.1007/s00520-021-06262-1DOI Listing
May 2021

Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5-fluorouracil and leucovorin combination as first- or second-line treatment against metastatic colorectal cancer: Results from the International EORTC 05011 Trial.

Int J Cancer 2020 Dec 3. Epub 2020 Dec 3.

Division of Medical Oncology, San Camillo Forlanini Hospital, Rome, Italy.

The triplet combination of irinotecan, oxaliplatin and fluorouracil is an active frontline regimen in metastatic colorectal cancer, but scarce data exist on its use as salvage treatment. We aimed at assessing its safety and efficacy profiles with its circadian-based administration (chronoIFLO5) as either first- or second-line treatment, within the time-finding EORTC 05011 trial. Five-day chronoIFLO5 was administered every 3 weeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180 mg/sqm), oxaliplatin (80 mg/sqm) and fluorouracil-leucovorin (2800 and 1200 mg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in first- and second-line settings. Primary endpoints included Grade 3-4 toxicity rates, best objective response rate (ORR), progression-free survival (PFS) and overall survival (OS). One-hundred forty-nine and 44 patients were treated in first-line and second-line settings, respectively, with a total of 1138 cycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirty-six (24.7%) and 10 (22.2%) patients experienced at least one episode of severe toxicity in first line and second line, respectively. Frontline chronoIFLO5 yielded an ORR of 62.3% [95% CI: 54.2-70.4] and resulted in median PFS and OS of 8.7 months [7.5-9.9] and 19.9 months [15.4-24.5]. Corresponding figures in second line were 37.5% [22.5-52.5], 6.7 months [4.8-8.9] and 16.3 months [11.8-20.8]. International and prospective evaluation revealed the favourable safety and efficacy profiles of chronoIFLO5, both as frontline and as salvage treatment against metastatic colorectal cancer. In particular, encouraging activity in second line was observed, with limited haematological toxicity.
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http://dx.doi.org/10.1002/ijc.33422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8048520PMC
December 2020

Hepatic metastases resection after cetuximab: are we missing something?

Lancet Oncol 2020 05;21(5):e228

Centre Hépato-Biliaire, Assistance Publique-Hopitaux de Paris, Paul Brousse Hospital, 94800 Villejuif, France; INSERM U935 Campus CNRS, Villejuif, France.

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http://dx.doi.org/10.1016/S1470-2045(20)30144-3DOI Listing
May 2020

Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer: Randomized multicenter EORTC 05011 trial.

Cancer Med 2020 06 22;9(12):4148-4159. Epub 2020 Apr 22.

Division of Biomedical Sciences, Cancer Chronotherapy Team, Cancer Research Centre, Warwick Medical School, Coventry, United Kingdom.

The least toxic time (LTT) of irinotecan varied by up to 8 hours according to sex and genetic background in mice. The translational relevance was investigated within a randomized trial dataset, where no LTT stood out significantly in the whole population. 130 male and 63 female eligible patients with metastatic colorectal cancer were randomized to receive chronomodulated Irinotecan with peak delivery rate at 1 of 6 clock hours staggered by 4 hours on day 1, then fixed-time chronomodulated Fluorouracil-Leucovorin-Oxaliplatin for 4 days, q3 weeks. The sex-specific circadian characteristics of grade (G) 3-4 toxicities were mapped with cosinor and time*sex interactions confirmed with Fisher's exact test. Baseline characteristics of male or female patients were similar in the six treatment groups. Main grade 3-4 toxicities over six courses were diarrhea (males vs females, 39.2%; vs 46.0%), neutropenia (15.6% vs 15.0%), fatigue (11.5% vs 15.9%), and anorexia (10.0% vs 7.8%). They were reduced following irinotecan peak delivery in the morning for males, but in the afternoon for females, with statistically significant rhythms (P < .05 from cosinor) and sex*timing interactions (Fisher's exact test, diarrhea, P = .023; neutropenia, P = .015; fatigue, P = .062; anorexia, P = .032). Irinotecan timing was most critical for females, with grades 3-4 ranging from 55.2% of the patients (morning) to 29.4% (afternoon) for diarrhea, and from 25.9% (morning) to 0% (afternoon) for neutropenia. The study results support irinotecan administration in the morning for males and in the afternoon for females, in order to minimize adverse events without impairing efficacy.
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http://dx.doi.org/10.1002/cam4.3056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300418PMC
June 2020

The day after: correlates of patient-reported outcomes with actigraphy-assessed sleep in cancer patients at home (inCASA project).

Sleep 2019 10;42(10)

Cancer Chronotherapy Team, Cancer Research Centre, Division of Biomedical Sciences, Warwick Medical School, Coventry, UK.

Subjective sleep assessment in cancer patients poorly correlates with actigraphy parameters that usually encompass multiple nights. We aimed to determine the objective actigraphy measures that best correlated with subjective sleep ratings on a night-by-night basis in cancer patients. Thirty-one cancer patients daily self-rated sleep disturbances using the single dedicated item of the MD Anderson Symptom Inventory (0-10 scale) with 18 other items, and continuously wore a wrist actigraph for 30 days. Objective sleep parameters were computed from the actigraphy nighttime series, and correlated with subjective sleep disturbances reported on the following day, using repeated measures correlations. Multilevel Poisson regression analysis was performed to identify the objective and subjective parameters that affected subjective sleep rating. Poor subjective sleep score was correlated with poor sleep efficiency (rrm = -0.13, p = 0.002) and large number of wake episodes (rrm = 0.12, p = 0.005) on the rated night. Multilevel analysis demonstrated that the expected sleep disturbance score was affected by the joint contribution of the wake episodes (exp(β) = 1.01, 95% confidence interval = 1.00 to 1.02, p = 0.016), fatigue (exp(β) = 1.35, 95% confidence interval = 1.15 to 1.55, p < 0.001) and drowsiness (exp(β) = 1.70, 95% confidence interval = 1.19 to 2.62, p = 0.018), self-rated the following evening, and sleep disturbance experienced one night before (exp(β) = 1.77, 95% confidence interval = 1.41 to 2.22, p < 0.001). The night-by-night approach within a multidimensional home tele-monitoring framework mainly identified the objective number of wake episodes computed from actigraphy records as the main determinant of the severity of sleep complaint in cancer patients on chemotherapy. This quantitative information remotely obtained in real time from cancer patients provides a novel framework for streamlining and evaluating interventions toward sleep improvement in cancer patients.
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http://dx.doi.org/10.1093/sleep/zsz146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587155PMC
October 2019

Circadian rest-activity rhythm as an objective biomarker of patient-reported outcomes in patients with advanced cancer.

Cancer Med 2018 09 7;7(9):4396-4405. Epub 2018 Aug 7.

Cancer Chronotherapy Team, Cancer Research Centre, Warwick Medical School, Coventry, UK.

Background: Psychosocial symptoms often cluster together, are refractory to treatment, and impair health-related quality of life (HR-QoL) in cancer patients. The contribution of circadian rhythm alterations to systemic symptoms has been overlooked in cancer, despite a causal link shown under jet lag and shift work conditions. We investigated whether the circadian rest-activity rhythm provides a reliable and objective estimate of the most frequent patient-reported outcome measures (PROMs).

Methods: Two datasets were used, each involving concomitant 3-day time series of wrist actigraphy and HR-QoL questionnaires: EORTC QLQ-C30 was completed once by 237 patients with metastatic colorectal cancer; MD Anderson Symptom Inventory (MDASI) was completed daily by 31 patients with advanced cancer on continuous actigraphy monitoring, providing 1015 paired data points. Circadian function was assessed using the clinically validated dichotomy index I < O. Nonparametric tests compared PROMs and I < O. Effect sizes were computed. Sensitivity subgroup and temporal dynamics analyses were also performed.

Results: I < O values were significantly lower with increasing symptom severity and worsening HR-QoL domains. Fatigue and anorexia were worse in patients with circadian disruption. The differences were both statistically and clinically significant (P < 0.001; d ≥ 0.33). Physical and social functioning, and global quality/enjoyment of life were significantly better in patients with robust circadian rhythm (P < 0.001; d ≥ 0.26). Sensitivity analyses validated these findings.

Conclusion: Objectively determined circadian disruption was consistently and robustly associated with clinically meaningfully severe fatigue, anorexia, and interference with physical and social functioning. This supports an important role of the circadian system in the determination of cancer patients' HR-QoL and symptoms that deserves therapeutic exploitation.
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http://dx.doi.org/10.1002/cam4.1711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143939PMC
September 2018

Systems Chronotherapeutics.

Pharmacol Rev 2017 04;69(2):161-199

Warwick Medical School (A.B., P.F.I., R.D., F.A.L.) and Warwick Mathematics Institute (A.B., D.A.R.), University of Warwick, Coventry, United Kingdom; Warwick Systems Biology and Infectious Disease Epidemiological Research Centre, Senate House, Coventry, United Kingdom (A.B., P.F.I., R.D., D.A.R., F.A.L.); INSERM-Warwick European Associated Laboratory "Personalising Cancer Chronotherapy through Systems Medicine" (C2SysMed), Unité mixte de Recherche Scientifique 935, Centre National de Recherche Scientifique Campus, Villejuif, France (A.B., P.F.I., R.D., D.A.R., F.A.L.); and Queen Elisabeth Hospital Birmingham, University Hospitals Birmingham National Health Service Foundation Trust, Cancer Unit, Edgbaston Birmingham, United Kingdom (P.F.I., F.A.L.).

Chronotherapeutics aim at treating illnesses according to the endogenous biologic rhythms, which moderate xenobiotic metabolism and cellular drug response. The molecular clocks present in individual cells involve approximately fifteen clock genes interconnected in regulatory feedback loops. They are coordinated by the suprachiasmatic nuclei, a hypothalamic pacemaker, which also adjusts the circadian rhythms to environmental cycles. As a result, many mechanisms of diseases and drug effects are controlled by the circadian timing system. Thus, the tolerability of nearly 500 medications varies by up to fivefold according to circadian scheduling, both in experimental models and/or patients. Moreover, treatment itself disrupted, maintained, or improved the circadian timing system as a function of drug timing. Improved patient outcomes on circadian-based treatments (chronotherapy) have been demonstrated in randomized clinical trials, especially for cancer and inflammatory diseases. However, recent technological advances have highlighted large interpatient differences in circadian functions resulting in significant variability in chronotherapy response. Such findings advocate for the advancement of personalized chronotherapeutics through interdisciplinary systems approaches. Thus, the combination of mathematical, statistical, technological, experimental, and clinical expertise is now shaping the development of dedicated devices and diagnostic and delivery algorithms enabling treatment individualization. In particular, multiscale systems chronopharmacology approaches currently combine mathematical modeling based on cellular and whole-body physiology to preclinical and clinical investigations toward the design of patient-tailored chronotherapies. We review recent systems research works aiming to the individualization of disease treatment, with emphasis on both cancer management and circadian timing system-resetting strategies for improving chronic disease control and patient outcomes.
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http://dx.doi.org/10.1124/pr.116.013441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394920PMC
April 2017

Phase locking and multiple oscillating attractors for the coupled mammalian clock and cell cycle.

Proc Natl Acad Sci U S A 2014 Jul 23;111(27):9828-33. Epub 2014 Jun 23.

Systems Biology Centre, University of Warwick, Coventry CV4 7AL, United Kingdom;

Daily synchronous rhythms of cell division at the tissue or organism level are observed in many species and suggest that the circadian clock and cell cycle oscillators are coupled. For mammals, despite known mechanistic interactions, the effect of such coupling on clock and cell cycle progression, and hence its biological relevance, is not understood. In particular, we do not know how the temporal organization of cell division at the single-cell level produces this daily rhythm at the tissue level. Here we use multispectral imaging of single live cells, computational methods, and mathematical modeling to address this question in proliferating mouse fibroblasts. We show that in unsynchronized cells the cell cycle and circadian clock robustly phase lock each other in a 1:1 fashion so that in an expanding cell population the two oscillators oscillate in a synchronized way with a common frequency. Dexamethasone-induced synchronization reveals additional clock states. As well as the low-period phase-locked state there are distinct coexisting states with a significantly higher period clock. Cells transition to these states after dexamethasone synchronization. The temporal coordination of cell division by phase locking to the clock at a single-cell level has significant implications because disordered circadian function is increasingly being linked to the pathogenesis of many diseases, including cancer.
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http://dx.doi.org/10.1073/pnas.1320474111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4103330PMC
July 2014

The circadian timing system in clinical oncology.

Ann Med 2014 Jun;46(4):191-207

INSERM, UMRS 776 'Biological Rhythms and Cancers', Campus CNRS , 7 rue Guy Môquet, 94801 Villejuif Cedex , France.

The circadian timing system (CTS) controls several critical molecular pathways for cancer processes and treatment effects over the 24 hours, including drug metabolism, cell cycle, apoptosis, and DNA damage repair mechanisms. This results in the circadian time dependency of whole-body and cellular pharmacokinetics and pharmacodynamics of anticancer agents. However, CTS robustness and phase varies among cancer patients, based on circadian monitoring of rest- activity, body temperature, sleep, and/or hormonal secretion rhythms. Circadian disruption has been further found in up to 50% of patients with metastatic cancer. Such disruption was associated with poor outcomes, including fatigue, anorexia, sleep disorders, and short progression-free and overall survival. Novel, minimally invasive devices have enabled continuous CTS assessment in non-hospitalized cancer patients. They revealed up to 12-hour differences in individual circadian phase. Taken together, the data support the personalization of chronotherapy. This treatment method aims at the adjustment of cancer treatment delivery according to circadian rhythms, using programmable-in-time pumps or novel release formulations, in order to increase both efficacy and tolerability. A fixed oxaliplatin, 5-fluorouracil and leucovorin chronotherapy protocol prolonged median overall survival in men with metastatic colorectal cancer by 3.3 months as compared to conventional delivery, according to a meta-analysis (P=0.009). Further analyses revealed the need for the prevention of circadian disruption or the restoration of robust circadian function in patients on chronotherapy, in order to further optimize treatment effects. The strengthening of external synchronizers could meet such a goal, through programmed exercise, meal timing, light exposure, improved social support, sleep scheduling, and the properly timed administration of drugs that target circadian clocks. Chrono-rehabilitation warrants clinical testing for improving quality of life and survival in cancer patients.
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http://dx.doi.org/10.3109/07853890.2014.916990DOI Listing
June 2014

Prediction of overall survival through circadian rest-activity monitoring during chemotherapy for metastatic colorectal cancer.

Int J Cancer 2012 Dec 3;131(11):2684-92. Epub 2012 Jul 3.

INSERM, UMRS 776, «Biological Rhythms and Cancers», Villejuif, France.

The clinical relevance of circadian rhythm modifications in patients on chemotherapy is unknown. Even so, circadian parameter I
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http://dx.doi.org/10.1002/ijc.27574DOI Listing
December 2012

Chronotherapy and the molecular clock: Clinical implications in oncology.

Adv Drug Deliv Rev 2010 Jul 23;62(9-10):979-1001. Epub 2010 Jun 23.

INSERM, Villejuif, France.

The circadian timing system drives daily rhythmic changes in drug metabolism and controls rhythmic events in cell cycle, DNA repair, apoptosis, and angiogenesis in both normal tissue and cancer. Rodent and human studies have shown that the toxicity and anticancer activity of common cancer drugs can be significantly modified by the time of administration. Altered sleep/activity rhythms are common in cancer patients and can be disrupted even more when anticancer drugs are administered at their most toxic time. Disruption of the sleep/activity rhythm accelerates cancer growth. The complex circadian time-dependent connection between host, cancer and therapy is further impacted by other factors including gender, inter-individual differences and clock gene polymorphism and/or down regulation. It is important to take circadian timing into account at all stages of new drug development in an effort to optimize the therapeutic index for new cancer drugs. Better measures of the individual differences in circadian biology of host and cancer are required to further optimize the potential benefit of chronotherapy for each individual patient.
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http://dx.doi.org/10.1016/j.addr.2010.06.002DOI Listing
July 2010

Circadian disruption, fatigue, and anorexia clustering in advanced cancer patients: implications for innovative therapeutic approaches.

Integr Cancer Ther 2009 Dec;8(4):361-70

INSERM, U776 Biological Rhythms and Cancers, Villejuif, France.

A disruption of the circadian timing system, as identified by monitoring of marker biorhythms, is common in cancer patients. The recording of the rest-activity rhythm with a wrist actigraph has been commonly used. This noninvasive monitoring allows a robust estimation of circadian disruption. The authors have previously found that altered patterns of circadian rest-activity rhythms are significantly and independently associated with the severity of fatigue and anorexia in patients with metastatic colorectal cancer. Elevated proinflammatory cytokines could partly account for this circadian disruption and its associated constitutional symptoms. Here, the authors present and discuss the data supporting the hypothesis that circadian disruption is often associated with fatigue and anorexia, which in turn further alter and dampen circadian synchronization, thus, creating a vicious cycle. This body of evidence paves the path for innovative therapeutic approaches targeting the circadian timing system in an effort to diminish constitutional symptoms induced by cancer and some anticancer treatments.
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http://dx.doi.org/10.1177/1534735409355293DOI Listing
December 2009

The circadian timing system: a coordinator of life processes: chronobiological investigations. Implications for the rhythmic delivery of cancer therapeutics.

Authors:
Francis A Lévi

IEEE Eng Med Biol Mag 2008 Jan-Feb;27(1):17-9

U 776 INSERM, Rythmes Biologiques et Cancers, Hôpital Paul Brousse, Villejuif, France.

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http://dx.doi.org/10.1109/MEMB.2007.907361DOI Listing
March 2008