Publications by authors named "Pasquale F Innominato"

45 Publications

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

The challenge of offering potentially curative treatment to patients with esophageal cancer and a history of liver transplantation: A literature review and case report.

Surgery 2021 Jun 21;169(6):1379-1385. Epub 2021 Jan 21.

Upper Gastrointestinal Surgery Unit, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom. Electronic address:

Background: With survival after liver transplantation continuing to improve, effective and evidence-based treatment of malignancies in this patient group is needed as a matter of urgency. Treatment outcomes for esophageal cancer, a challenging malignancy to treat in otherwise fit and well patients, after liver transplant are rarely reported.

Methods: A systematic literature review was performed according to the PRISMA guidance to identify studies reporting outcomes of radical esophageal cancer treatment in patients with liver transplant. Management strategies and oncological outcomes were compared with a case managed at our institution.

Results: Six studies were identified for review, and the outcomes of 13 patients were collated. The most common indication for liver transplant was alcohol-related liver disease (62%), and the most common tumor type was adenocarcinoma (54%). Neoadjuvant chemotherapy was delivered safely in 23% of cases in the literature and in the case managed at our institution. The median time from liver transplant to esophagectomy was 46 months, and the majority of patients underwent an Ivor-Lewis esophagectomy. The median follow-up from esophagectomy was 17 months, with a pooled 1-year survival of 77% and recurrence rate of 38%. This was comparable with corresponding rates reported for nontransplanted patients.

Conclusion: This case report and systematic review demonstrates that radical treatment of esophageal cancer after liver transplantation is not only technically feasible when managed by expert multidisciplinary teams but that it also improves survival. Routine surveillance of liver transplant patients with evidence of Barrett's preoperatively should be considered and close involvement of appropriate specialists in individual treatment planning is vital to acceptable outcomes.
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http://dx.doi.org/10.1016/j.surg.2020.12.015DOI Listing
June 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

A retrospective study of patient-tailored FOLFIRINOX as a first-line chemotherapy for patients with advanced biliary tract cancer.

BMC Cancer 2020 Jun 3;20(1):515. Epub 2020 Jun 3.

INSERM U935 Campus CNRS, Villejuif, France.

Background: FOLFIRINOX is a pillar first-line regimen in the treatment of pancreatic cancer. Historically, biliary tract cancer (BTC) and pancreatic cancer have been treated similarly with gemcitabine alone or combined with a platinum compound. With growing evidence supporting the role of fluoropyrimidines in the treatment of BTC, we aimed at assessing the outcomes of patients (pts) with BTC on frontline FOLFIRINOX.

Methods: We retrospectively analyzed data of all our consecutive patients with locally advanced (LA) or metastatic (M) BTC who were registered to receive FOLFIRINOX as a first-line therapy between 12/2013 and 11/2017 at Paul Brousse university hospital. The main endpoints were Overall Survival (OS), Time-to-Progression (TTP), best Objective Response Rate (ORR), Disease Control rate (DCR), secondary macroscopically-complete resection (res) and incidence of severe (grade 3-4) toxicity (tox).

Results: There were 17 male (40%) and 25 female (60%) pts. aged 36 to 84 years (median: 67). They had PS of 0 (55%) or 1 (45%), and intrahepatic cholangiocarcinoma (CCA) (21 pts., 50%), gallbladder carcinoma (8 pts., 19%), perihilar CCA (7 pts., 17%), distal CCA (4 pts., 10%) and ampulloma (2 pts., 5%). BTC was LA or M in 10 (24%) and 32 pts. (76%) respectively. Biliary stent was placed in 14 pts. (33%). A median of 10 courses was given with median treatment duration of 6 months. There were no untoward toxicity issues, with no febrile neutropenia, emergency admission for toxicity or toxic death. We observed 12 partial responses (29%) and 19 disease stabilisations (45%). Six patients (14%) underwent secondary R0-R1 resection. Median TTP was 8 months [95%CL, 6-10] and median OS was 15 months [13-17]. Patients undergoing secondary resection displayed a 3-y disease-free rate of 83%.

Conclusions: First-line FOLFIRINOX offers promising results in patients with LA and M-BTC. It deserves prospective evaluation to further improve outcomes for advanced BTC.
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http://dx.doi.org/10.1186/s12885-020-07004-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268699PMC
June 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

Does circadian rhythm influence gastrointestinal toxicity?

Curr Opin Support Palliat Care 2020 06;14(2):120-126

North Wales Cancer Centre, Ysbyty Gwynedd, Betsi Cadwaladr University Health Board, Bangor.

Purpose Of Review: The current review outlines the existing research on the impact of circadian rhythm on gastrointestinal toxicity associated with cancer treatment and explores clinical evidence for utilizing circadian-based approaches in addressing gastrointestinal symptoms such as nausea, vomiting, diarrhea, mucositis, and hepatotoxicity.

Recent Findings: Recent evidence highlights circadian control of gastrointestinal physiology of appetite, digestion, nutrient absorption, and cellular proliferation in the digestive system. In addition, animal models support the mechanistic rationale of using chronotherapy (a type of anticancer therapy delivered at specific times with the goal of producing less toxicity and greater treatment response) to minimize gastrointestinal-impact of systemic cancer treatments. In addition, earlier research demonstrates that many chemotherapeutic agents are responsive to circadian timing in animals. On the contrary, clinical trials focused on minimizing gastrointestinal toxicity using chronotherapy have been limited in recent years and have not yielded the efficacy initially hoped for. Instead, researchers focused on understanding circadian rhythm's influence on the gastrointestinal system at a mechanistic level as well as measuring circadian rhythm at an individual level.

Summary: Although using circadian timing is a promising target for reducing gastrointestinal toxicity, recent evidence suggests that more research is needed to understand circadian rhythm before circadian-based interventions can be developed that will result in lessening of gastrointestinal toxicity.
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http://dx.doi.org/10.1097/SPC.0000000000000498DOI Listing
June 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

A novel approach to management of sleep-associated problems in patients with breast cancer (MOSAIC) during chemotherapy : A pilot study.

Sleep 2020 10;43(10)

Cancer Neuroscience Laboratory, School of Nursing, University of Texas at Austin, Austin, TX.

Study Objectives: This pilot randomized controlled trial (RCT) was conducted to assess the preliminary effects of Brief Behavioral Therapy for Cancer-Related Insomnia (BBT-CI) delivered by trained research staff in comparison to a sleep hygiene pamphlet control and to assess moderators of treatment effect in patients with breast cancer undergoing chemotherapy.

Methods: Of 74 participants recruited, 37 were randomized to BBT-CI and 37 were randomized to the control condition. Trained staff members delivered the intervention during chemotherapy treatments to reduce patients' burden. Insomnia was assessed with the Insomnia Severity Index (ISI), anxiety was assessed with the Spielberger State-Trait Anxiety Inventory, symptom burden was assessed with the Symptom Inventory (SI), and study staff recorded previous treatments and surgeries received by patients.

Results: Patients randomized to BBT-CI showed significantly greater improvements in their ISI scores compared to the sleep hygiene group. Additionally, several treatment moderators were identified. The effect of BBT-CI was greater among individuals with lower baseline state-trait anxiety, with previous surgery for cancer, and with higher baseline somatic symptom severity.

Conclusions: BBT-CI shows preliminary efficacy compared to the sleep hygiene handout on insomnia in cancer patients undergoing chemotherapy. A large-phase III RCT needs to be conducted to replicate the preliminary findings.
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http://dx.doi.org/10.1093/sleep/zsaa070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755138PMC
October 2020

Optimizing circadian drug infusion schedules towards personalized cancer chronotherapy.

PLoS Comput Biol 2020 01 27;16(1):e1007218. Epub 2020 Jan 27.

INSERM and Paris Sud university, UMRS 935, Team "Cancer Chronotherapy and Postoperative Liver Functions", Campus CNRS, Villejuif, F-94807, France. & Honorary position, University of Warwick, UK.

Precision medicine requires accurate technologies for drug administration and proper systems pharmacology approaches for patient data analysis. Here, plasma pharmacokinetics (PK) data of the OPTILIV trial in which cancer patients received oxaliplatin, 5-fluorouracil and irinotecan via chronomodulated schedules delivered by an infusion pump into the hepatic artery were mathematically investigated. A pump-to-patient model was designed in order to accurately represent the drug solution dynamics from the pump to the patient blood. It was connected to semi-mechanistic PK models to analyse inter-patient variability in PK parameters. Large time delays of up to 1h41 between the actual pump start and the time of drug detection in patient blood was predicted by the model and confirmed by PK data. Sudden delivery spike in the patient artery due to glucose rinse after drug administration accounted for up to 10.7% of the total drug dose. New model-guided delivery profiles were designed to precisely lead to the drug exposure intended by clinicians. Next, the complete mathematical framework achieved a very good fit to individual time-concentration PK profiles and concluded that inter-subject differences in PK parameters was the lowest for irinotecan, intermediate for oxaliplatin and the largest for 5-fluorouracil. Clustering patients according to their PK parameter values revealed patient subgroups for each drug in which inter-patient variability was largely decreased compared to that in the total population. This study provides a complete mathematical framework to optimize drug infusion pumps and inform on inter-patient PK variability, a step towards precise and personalized cancer chronotherapy.
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http://dx.doi.org/10.1371/journal.pcbi.1007218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004559PMC
January 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 Biology, Systems Medicine, Systems Pharmacology: The What and The Why.

Acta Biotheor 2018 Dec 9;66(4):345-365. Epub 2018 May 9.

INSERM and Université Paris 11 Unit 935, Villejuif, France.

Systems biology is today such a widespread discipline that it becomes difficult to propose a clear definition of what it really is. For some, it remains restricted to the genomic field. For many, it designates the integrated approach or the corpus of computational methods employed to handle the vast amount of biological or medical data and investigate the complexity of the living. Although defining systems biology might be difficult, on the other hand its purpose is clear: systems biology, with its emerging subfields systems medicine and systems pharmacology, clearly aims at making sense of complex observations/experimental and clinical datasets to improve our understanding of diseases and their treatments without putting aside the context in which they appear and develop. In this short review, we aim to specifically focus on these new subfields with the new theoretical tools and approaches that were developed in the context of cancer. Systems pharmacology and medicine now give hope for major improvements in cancer therapy, making personalized medicine closer to reality. As we will see, the current challenge is to be able to improve the clinical practice according to the paradigm shift of systems sciences.
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http://dx.doi.org/10.1007/s10441-018-9330-2DOI Listing
December 2018

Relevance of a Mobile Internet Platform for Capturing Inter- and Intrasubject Variabilities in Circadian Coordination During Daily Routine: Pilot Study.

J Med Internet Res 2018 06 11;20(6):e204. Epub 2018 Jun 11.

Cancer Chronotherapy Team, School of Medicine, University of Warwick, Coventry, United Kingdom.

Background: Experimental and epidemiologic studies have shown that circadian clocks' disruption can play an important role in the development of cancer and metabolic diseases. The cellular clocks outside the brain are effectively coordinated by the body temperature rhythm. We hypothesized that concurrent measurements of body temperature and rest-activity rhythms would assess circadian clocks coordination in individual patients, thus enabling the integration of biological rhythms into precision medicine.

Objective: The objective was to evaluate the circadian clocks' coordination in healthy subjects and patients through simultaneous measurements of rest-activity and body temperature rhythms.

Methods: Noninvasive real-time measurements of rest-activity and chest temperature rhythms were recorded during the subject's daily life, using a dedicated new mobile electronic health platform (PiCADo). It involved a chest sensor that jointly measured accelerations, 3D orientation, and skin surface temperature every 1-5 min and relayed them out to a mobile gateway via Bluetooth Low Energy. The gateway tele-transmitted all stored data to a server via General Packet Radio Service every 24 hours. The technical capabilities of PiCADo were validated in 55 healthy subjects and 12 cancer patients, whose rhythms were e-monitored during their daily routine for 3-30 days. Spectral analyses enabled to compute rhythm parameters values, with their 90% confidence limits, and their dynamics in each subject.

Results: All the individuals displayed a dominant circadian rhythm in activity with maxima occurring from 12:09 to 20:25. This was not the case for the dominant temperature period, which clustered around 24 hours for 51 out of 67 subjects (76%), and around 12 hours for 13 others (19%). Statistically significant sex- and age-related differences in circadian coordination were identified in the noncancerous subjects, based upon the range of variations in temperature rhythm amplitudes, maxima (acrophases), and phase relations with rest-activity. The circadian acrophase of chest temperature was located at night for the majority of people, but it occurred at daytime for 26% (14/55) of the noncancerous people and 33% (4/12) of the cancer patients, thus supporting important intersubject differences in circadian coordination. Sex, age, and cancer significantly impacted the circadian coordination of both rhythms, based on their phase relationships.

Conclusions: Complementing rest-activity with chest temperature circadian e-monitoring revealed striking intersubject differences regarding human circadian clocks' coordination and timing during daily routine. To further delineate the clinical importance of such finding, the PiCADo platform is currently applied for both the assessment of health effects resulting from atypical work schedules and the identification of the key determinants of circadian disruption in cancer patients.
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http://dx.doi.org/10.2196/jmir.9779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018238PMC
June 2018

Impact of country of birth on genetic testing of metastatic lung adenocarcinomas in France: African women exhibit a mutational spectrum more similar to Asians than to Caucasians.

Oncotarget 2017 Aug 7;8(31):50792-50803. Epub 2017 Feb 7.

AP-HP, GH Paris-Sud, Hôpital Paul Brousse, Department of Biochiemistry and Oncogenetics, Platform Oncomolpath/INCa, Villejuif, France.

Background: Limited data are available on the prevalence of oncogenic driver mutations in Caucasian populations, and especially in Europeans.

Aim: To evaluate the targetable mutational spectra in unselected patients with lung adenocarcinoma in routine clinical practice from several French hospitals, using the same molecular platform.

Patients And Methods: Samples from 2,219 consecutive patients with histologically-proven advanced lung adenocarcinoma were centrally analysed at a referenced and certified diagnostic platform in order to test for activating and resistance mutations in , , , and . Demographic and clinical features were retrieved from the medical charts. Multivariate binary logistic regression was used to determine the independent predictive factors for the occurrence of specific mutations, in the whole study population or in selected subgroups.

Findings: The overall respective incidence of , , , and mutations was 10.5%, 0.9%, 25%, 1.5%, 2.1% and 1.4%, in our study sample including 87.4% white Caucasians, 10.8% Africans and 1.8% Asians; 60.6% men, 30.7% never smoker (median age: 68.3 years). Ethnicity was an independent predictor for EGFR, KRAS and ERBB2 gene abnormalities. In all cases, a significantly higher prevalence of targetable and , and a lower prevalence of resistance mutations were observed in African women as compared to African men or Caucasians.

Conclusions: In real life conditions of routine genetic testing, we have identified subsets of patients with specific targetable activating somatic mutations according to ethnicity, who could preferentially benefit from anti- and anti- targeted therapies.
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http://dx.doi.org/10.18632/oncotarget.15132DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5584205PMC
August 2017

Relationship between subjective and actigraphy-measured sleep in 237 patients with metastatic colorectal cancer.

Qual Life Res 2017 10 27;26(10):2783-2791. Epub 2017 Jun 27.

Cancer Chronotherapy Unit, Cancer Research Centre, Warwick Medical School, Coventry, Warwickshire, UK.

Objective: Patients with cancers frequently experience sleep and circadian dysfunction. To date, only a few studies have used both a questionnaire and actigraphy for concomitant evaluation of sleep and circadian function in patients with cancer. We sought to evaluate objective sleep and circadian parameters in metastatic colon cancer (MCC) patients and their associations with symptoms and quality of life (QOL).

Methods: Patients reported subjective sleep problems on the EORTC QLQ-C30. Sleep and circadian parameters were calculated using a wrist-actigraph that patients wore for 72 h.

Results: 237 Patients with MCC (mean age: 60.4 years; range: 20.7-77.6; Male/Female ratio: 1.66) participated in this cross-sectional study. Subjective sleep problems were reported by 63.4% of patients (S+). No differences in any sleep parameters (sleep efficiency, sleep latency, total sleep time, total time in bed, wake after sleep onset, activity bathyphase) were observed between S+ and S- patients. However, S+ patients displayed a significantly worse circadian function than S- patients (96.4 vs 98.1%; p = 0.005). The presence of poor subjective sleep and objective circadian dysfunction negatively affected symptoms and QOL domains (p = 0.038).

Conclusions: Subjective report of sleep problems was not associated with worse objectively measured sleep parameters in patients with MCC although it was associated with disrupted circadian rest-activity rhythm and poorer QOL. These findings coincide with prior research in cancer patients in that an inconsistent relationship exists between subjective and objective sleep measurements on some sleep domains. This study supports the value of coupled evaluation of self-reported and objective measures of sleep and circadian function in cancer patients.
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http://dx.doi.org/10.1007/s11136-017-1617-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5711611PMC
October 2017

Resection of colorectal liver metastases after second-line chemotherapy: is it worthwhile? A LiverMetSurvey analysis of 6415 patients.

Eur J Cancer 2017 06 10;78:7-15. Epub 2017 Apr 10.

Division of Surgery A, Department of Surgery, GB Rossi Hospital, University of Verona, Verona, Italy.

Purpose: Patient outcome after resection of colorectal liver metastases (CLM) following second-line preoperative chemotherapy (PCT) performed for insufficient response or toxicity of the first-line, is little known and has here been compared to the outcome following first-line.

Patients And Methods: From January 2005 to June 2013, 5624 and 791 consecutive patients of a prospective international cohort received 1 and 2 PCT lines before CLM resection (group 1 and 2, respectively). Survival and prognostic factors were analysed.

Results: After a mean follow-up of 30.1 months, there was no difference in survival from CLM diagnosis (median, 3-, and 5-year overall survival [OS]: 58.6 months, 76% and 49% in group 2 versus 58.9 months, 71% and 49% in group 1, respectively, P = 0.32). After hepatectomy, disease-free survival (DFS) was however shorter in group 2: 17.2 months, 27% and 15% versus 19.4 months, 32% and 23%, respectively (P = 0.001). Among the initially unresectable patients of group 1 and 2, no statistical difference in OS or DFS was observed. Independent predictors of worse OS in group 2 were positive primary lymph nodes, extrahepatic disease, tumour progression on second line, R2 resection and number of hepatectomies/year <50. Positive primary nodes, synchronous and bilateral metastases were predictors of shorter DFS. Initial unresectability did not impact OS or DFS in group 2.

Conclusion: CLM resection following second-line PCT, after oncosurgically favourable selection, could bring similar OS compared to what observed after first-line. For initially unresectable patients, OS or DFS is comparable between first- and second-line PCT. Surgery should not be denied after the failure of first-line chemotherapy.
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http://dx.doi.org/10.1016/j.ejca.2017.03.009DOI Listing
June 2017

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

Clinical Relevance of the First Domomedicine Platform Securing Multidrug Chronotherapy Delivery in Metastatic Cancer Patients at Home: The inCASA European Project.

J Med Internet Res 2016 11 25;18(11):e305. Epub 2016 Nov 25.

Cancer Chronotherapy Unit, Cancer Research Centre, Warwick Medical School, Coventry, United Kingdom.

Background: Telehealth solutions can improve the safety of ambulatory chemotherapy, contributing to the maintenance of patients at their home, hence improving their well-being, all the while reducing health care costs. There is, however, need for a practicable multilevel monitoring solution, encompassing relevant outputs involved in the pathophysiology of chemotherapy-induced toxicity. Domomedicine embraces the delivery of complex care and medical procedures at the patient's home based on modern technologies, and thus it offers an integrated approach for increasing the safety of cancer patients on chemotherapy.

Objective: The objective was to evaluate patient compliance and clinical relevance of a novel integrated multiparametric telemonitoring domomedicine platform in cancer patients receiving multidrug chemotherapy at home.

Methods: Self-measured body weight, self-rated symptoms using the 19-item MD Anderson Symptom Inventory (MDASI), and circadian rest-activity rhythm recording with a wrist accelerometer (actigraph) were transmitted daily by patients to a server via the Internet, using a dedicated platform installed at home. Daily body weight changes, individual MDASI scores, and relative percentage of activity in-bed versus out-of-bed (I
Results: A total of 31 patients (males: 55% [17/31]; World Health Organization Performance Status=0: 29% (9/31); age range: 35-91 years) participated for a median of 58 days (38-313). They received a total of 102 chemotherapy courses (64.7% as outpatients). Overall full compliance was 59.7% (522/874), with at least one data available for 830/874 patient-days (95.0%), during the 30-day per-protocol span. Missing data rates were similar for each parameter. Patients were altogether satisfied with the use of the platform. Ten toxicity-related hospitalizations occurred in 6 patients. The combination of weighted circadian function (actigraphy parameter I
Conclusions: Multidimensional daily telemonitoring of body weight, circadian rest-activity rhythm, and patient-reported symptoms was feasible, satisfactory, and clinically relevant in patients on chemotherapy. This domomedicine platform constitutes a unique tool for the further development of safe home-based chemotherapy administration.
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http://dx.doi.org/10.2196/jmir.6303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5148811PMC
November 2016

Relevance of internal time and circadian robustness for cancer patients.

BMC Cancer 2016 Apr 21;16:285. Epub 2016 Apr 21.

Chronobiology Laboratory, Department of Physiology, University of Murcia, IMIB-Arrixaca, Murcia, Spain.

Background: Adequate circadian timing of cancer treatment schedules (chronotherapy) can enhance tolerance and efficacy several-fold in experimental and clinical situations. However, the optimal timing varies according to sex, genetic background and lifestyle. Here, we compute the individual phase of the Circadian Timing System to decipher the internal timing of each patient and find the optimal treatment timing.

Methods: Twenty-four patients (11 male; 13 female), aged 36 to 77 years, with advanced or metastatic gastro-intestinal cancer were recruited. Inner wrist surface Temperature, arm Activity and Position (TAP) were recorded every 10 min for 12 days, divided into three 4-day spans before, during and after a course of a set chronotherapy schedule. Pertinent indexes, I < O and a new biomarker, DI (degree of temporal internal order maintenance), were computed for each patient and period.

Results: Three circadian rhythms and the TAP rhythm grew less stable and more fragmented in response to treatment. Furthermore, large inter- and intra-individual changes were found for T, A, P and TAP patterns, with phase differences of up to 12 hours among patients. A moderate perturbation of temporal internal order was observed, but the administration of fixed chronomodulated chemotherapy partially resynchronized temperature and activity rhythms by the end of the study.

Conclusions: The integrated variable TAP, together with the asynchrony among rhythms revealed by the new biomarker DI, would help in the personalization of cancer chronotherapy, taking into account individual circadian phase markers.
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http://dx.doi.org/10.1186/s12885-016-2319-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4839139PMC
April 2016

The effect of melatonin on sleep and quality of life in patients with advanced breast cancer.

Support Care Cancer 2016 Mar 11;24(3):1097-105. Epub 2015 Aug 11.

Division of Medical Oncology, Sunnybrook Odette Cancer Centre, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada.

Background: Fatigue and sleep problems are prevalent in cancer patients and can be associated with disruption of circadian rhythmicity. In this prospective phase II trial, we sought to assess the effect of melatonin on circadian biomarkers, sleep, and quality of life in breast cancer patients.

Methods: Thirty-two patients with metastatic breast cancer, receiving hormonal or trastuzumab therapy, took 5 mg of melatonin at bedtime for 2 months. Before starting and after 2 months on melatonin therapy, sleep and circadian rhythmicity were assessed by actigraphy, diurnal patterns of serum cortisol, and the expression of the core clock genes PER2 and BMAL1 in peripheral blood mononuclear cells. The European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 questionnaire was completed for subjective parameters.

Results: Bedtime melatonin was associated with a significant improvement in a marker of objective sleep quality, sleep fragmentation and quantity, subjective sleep, fatigue severity, global quality of life, and social and cognitive functioning scales. Morning clock gene expression was increased following bedtime melatonin intake. Melatonin did not affect actigraphy measure of circadian rhythmicity, or the diurnal cortisol pattern.

Conclusion: These results invite further investigation of melatonin as a potentially useful therapeutic agent for improving sleep and quality of life in cancer patients.
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http://dx.doi.org/10.1007/s00520-015-2883-6DOI Listing
March 2016

The difference between in bed and out of bed activity as a behavioral marker of cancer patients: A comparative actigraphic study.

Chronobiol Int 2015 ;32(7):925-33

a Department of Psychology , University of Bologna , Bologna , Italy .

The current study was conducted to provide normative data on actigraphic dichotomy index (I < O) (the percentage of in bed activity counts that are less than the median of out of bed counts) in healthy population and to assess whether the I < O could be an effective index in discriminating the circadian motor activity of cancer patients from healthy controls. In this retrospective study, we recovered 408 actigraphic records from two databases: healthy controls (n = 182; 79 males; mean age 38.7 ± 12.6) and patients with metastatic colorectal cancer (n = 226; 149 males; mean age 58.4 ± 11.4). Beside the usual actigraphic sleep parameters (time in bed, sleep onset latency, total sleep time, wake after sleep onset, sleep efficiency, number of awakenings, and mean motor activity), we also computed the dichotomy index and number of actigraphic wake parameters, namely, diurnal motor activity, diurnal total sleep time, number of sleep episodes, and the mean duration of the longest diurnal sleep episode. Using the Youden index, we calculated the cut off value that performed the best for I < O and actigraphic wake parameters. Finally, we created Receiver Operator Characteristic curves to test the efficacy of each actigraphic parameter to discriminate cancer patient from healthy controls. Mean I < O was 99.5% (SD, 0.48%) in the healthy group, as compared to 96.6% (SD, 3.6%) in the cancer group (p < 0.0001). Important age-related effects appeared unlikely after performing both the main analysis with age as a covariate, and a subset analysis in 104 subjects matched for age and sex. In the main analysis, all actigraphic parameters, except total sleep time, significantly differentiated the two groups of participants. However, the I < O was the one that clearly performed best. Here, we provide the first large dataset on I < O in healthy subjects, we confirm the relevance of this circadian index for discriminating advanced stage colorectal cancer patients from healthy subjects, and we lay the grounds for further investigations of this circadian index in patients with other chronic diseases.
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http://dx.doi.org/10.3109/07420528.2015.1053909DOI Listing
May 2016

Subjective sleep and overall survival in chemotherapy-naïve patients with metastatic colorectal cancer.

Sleep Med 2015 Mar 22;16(3):391-8. Epub 2015 Jan 22.

Center for Stress and Health, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA; Stanford Cancer Institute, Stanford, CA, USA.

Backround: Sleep disorders are prevalent in patients with advanced cancer. Their impact on clinical outcomes is not well understood.

Methods: A post-hoc analysis was conducted in 361 chemo-naïve patients with metastatic colorectal cancer completing twice the EORTC QLQ-C30 questionnaire within a randomized international phase III trial. The study assessed the effect on overall survival (OS) of subjective sleep complaint, used as a normal or a time-dependent covariate (TDC), using a multivariate Cox proportional hazard model. Prognostic analysis was conducted on the whole study population and separately in each treatment arm (conventional FOLFOX2, or chronomodulated chronoFLO4).

Results: Sleep problems were reported by 202 patients (56%) at baseline and by 188 (52%) on treatment. Sleep problems at baseline were independently associated with a higher risk of earlier death (HR: 1.36; p = 0.011), progression (HR: 1.43; p = 0.002) and poor treatment response (RR: 0.58; p = 0.016). TDC analysis confirmed the independent prognostic effect of sleep problems on OS (HR: 1.37; p = 0.008), while on treatment this effect was only observed using univariate analysis. The negative prognostic value of sleep problems on OS at baseline, on treatment, and as a TDC was greatest on chronoFLO4 compared to FOLFOX2.

Conclusions: Subjective sleep problems are associated with poor clinical outcomes in metastatic colorectal cancer patients and affect chronotherapy effectiveness. There is a need for a well-tuned circadian timing system in order to increase chronotherapy activity. Prospective studies are needed for determining the impact of therapeutic approaches on sleep disorders upon quality of life and survival of cancer patients.
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http://dx.doi.org/10.1016/j.sleep.2014.10.022DOI Listing
March 2015

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

The circadian rest-activity rhythm, a potential safety pharmacology endpoint of cancer chemotherapy.

Int J Cancer 2014 Jun 25;134(11):2717-25. Epub 2013 Nov 25.

Department of Physiology Chronobiology Laboratory, University of Murcia, Murcia, Spain; INSERM, UMRS776, Biological Rhythms and Cancers, Villejuif, France.

The robustness of the circadian timing system (CTS) was correlated to quality of life and predicted for improved survival in cancer patients. However, chemotherapy disrupted the CTS according to dose and circadian timing in mice. A continuous and repeated measures longitudinal design was implemented here to characterize CTS dynamics in patients receiving a fixed circadian-based chemotherapy protocol. The rest-activity rhythm of 49 patients with advanced cancer was monitored using a wrist actigraph for 13 days split into four consecutive spans of 3-4 days each, i.e., before, during, right after and late after a fixed chronotherapy course. The relative amount of activity in bed vs. out of bed (I
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http://dx.doi.org/10.1002/ijc.28587DOI Listing
June 2014

Sleep disruption in breast cancer patients and survivors.

J Natl Compr Canc Netw 2013 Dec;11(12):1523-30

From the aDepartment of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California; bAPHP, Department of Oncology, Paul Brousse Hospital, Villejuif, France; cChronobiology Laboratory, Department of Physiology, Faculty of Biology, University of Murcia, Murcia, Spain; dINSERM UMRS776 "Biological Rhythms and Cancers," Villejuif, France; eLaboratory of Nutrition and Integrative Neurobiology (NutriNeuro), INRA 1286, Bordeaux, France; and fUniversity of Bordeaux, Bordeaux, France.

Sleep disruption is prevalent in patients and survivors of breast cancer. Most patients undergoing chemotherapy will experience transient sleep disruption, and nearly 60% will have chronic sleep problems. Numerous factors contribute to sleep disruption in women diagnosed with breast cancer. Sleep disruption is a consequence of several biological alterations, including circadian disruption and immune and metabolic deregulations. These systems also play significant roles in the control and progression of breast cancer. Sleep disruption is associated with many side effects and psychiatric and medical comorbidities. This article discusses the relationship between stress and posttraumatic stress disorder, depression and fatigue, and how sleep disturbance might be the cause or consequence of these disorders. Current evidence for management of sleep disturbance in breast cancer and high chronic use of hypnotic medication in this population is also discussed. Finally, the differences in management of sleep disturbance during acute cancer care and during the survivorship phase are discussed. More research is needed on accurate and timely assessment of sleep disturbance associated with breast cancer, and additional tailored approaches for the management of sleep problems in breast cancer should be developed.
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http://dx.doi.org/10.6004/jnccn.2013.0179DOI Listing
December 2013

Fatigue and weight loss predict survival on circadian chemotherapy for metastatic colorectal cancer.

Cancer 2013 Jul 30;119(14):2564-73. Epub 2013 Apr 30.

National Institute for Health and Medical Research (INSERM) Unit 776, "Biological Rhythms and Cancers," Villejuif, France.

Background: Chemotherapy-induced neutropenia has been associated with prolonged survival selectively in patients on a conventional schedule (combined 5-fluorouracil, leucovorin, and oxaliplatin [FOLFOX2]) but not on a chronomodulated schedule of the same drugs administered at specific circadian times (chronoFLO4). The authors hypothesized that the early occurrence of chemotherapy-induced symptoms correlated with circadian disruption would selectively hinder the efficacy of chronotherapy.

Methods: Fatigue and weight loss (FWL) were considered to be associated with circadian disruption based on previous data. Patients with metastatic colorectal cancer (n = 543) from an international phase 3 trial comparing FOLFOX2 with chronoFLO4 were categorized into 4 subgroups according to the occurrence of FWL or other clinically relevant toxicities during the initial 2 courses of chemotherapy. Multivariate Cox models were used to assess the role of toxicity on the time to progression (TTP) and overall survival (OS).

Results: The proportions of patients in the 4 subgroups were comparable in both treatment arms (P = .77). No toxicity was associated with TTP or OS on FOLFOX2. The median OS on FOLFOX2 ranged from 16.4 (95% confidence limits [CL], 7.2-25.6 months) to 19.8 months (95% CL, 17.7-22.0 months) according to toxicity subgroup (P = .45). Conversely, FWL, but no other toxicity, independently predicted for significantly shorter TTP (P < .0001) and OS (P = .001) on chronoFLO4. The median OS on chronoFLO4 was 13.8 months (95% CL, 10.4-17.2 months) or 21.1 months (95% CL, 19.0-23.1 months) according to presence or absence of chemotherapy-induced FWL, respectively.

Conclusions: Early onset chemotherapy-induced FWL was an independent predictor of poor TTP and OS only on chronotherapy. Dynamic monitoring to detect early chemotherapy-induced circadian disruption could allow the optimization of rapid chronotherapy and concomitant improvements in safety and efficacy.
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http://dx.doi.org/10.1002/cncr.28072DOI Listing
July 2013

Prevalence, putative mechanisms, and current management of sleep problems during chemotherapy for cancer.

Nat Sci Sleep 2012 Dec;4:151-162

Stanford University School of Medicine, Stanford, CA, USA.

Sleep problems are highly prevalent in cancer patients undergoing chemotherapy. This article reviews existing evidence on etiology, associated symptoms, and management of sleep problems associated with chemotherapy treatment during cancer. It also discusses limitations and methodological issues of current research. The existing literature suggests that subjectively and objectively measured sleep problems are the highest during the chemotherapy phase of cancer treatments. A possibly involved mechanism reviewed here includes the rise in the circulating proinflammatory cytokines and the associated disruption in circadian rhythm in the development and maintenance of sleep dysregulation in cancer patients during chemotherapy. Various approaches to the management of sleep problems during chemotherapy are discussed with behavioral intervention showing promise. Exercise, including yoga, also appear to be effective and safe at least for subclinical levels of sleep problems in cancer patients. Numerous challenges are associated with conducting research on sleep in cancer patients during chemotherapy treatments and they are discussed in this review. Dedicated intervention trials, methodologically sound and sufficiently powered, are needed to test current and novel treatments of sleep problems in cancer patients receiving chemotherapy. Optimal management of sleep problems in patients with cancer receiving treatment may improve not only the well-being of patients, but also their prognosis given the emerging experimental and clinical evidence suggesting that sleep disruption might adversely impact treatment and recovery from cancer.
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http://dx.doi.org/10.2147/NSS.S18895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3593248PMC
December 2012

Impact of paroxetine on sleep problems in 426 cancer patients receiving chemotherapy: a trial from the University of Rochester Cancer Center Community Clinical Oncology Program.

Sleep Med 2012 Oct 2;13(9):1184-90. Epub 2012 Aug 2.

Department of Psychiatry & Behavioral Sciences, Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA, USA.

Background: Sleep problems are a frequent distressing symptom in cancer patients, yet little is known about their treatment. Sleep problems and depression frequently co-occur, leading healthcare professionals to treat depression with the expectation that sleep problems will also improve. The purpose of this study was to compare the effect of paroxetine to placebo on sleep problems via a secondary data analysis of a RCT designed to compare the effects of paroxetine to placebo on fatigue in cancer patients undergoing chemotherapy. A previously published report found a significant effect of paroxetine on depression in this cohort.

Methods: A total of 426 patients were randomized following Cycle 2 of chemotherapy to receive either 20mg of paroxetine or placebo. Sleep problems were assessed using questions from the Hamilton Depression Inventory three times during chemotherapy.

Results: A total of 217 patients received paroxetine and 209 received placebo. Significantly fewer patients taking paroxetine reported sleep problems compared to patients on placebo (Paroxetine 79% versus Placebo 88%; p<0.05). These differences remained significant even after controlling for baseline sleep problems and depression (p<0.05).

Conclusion: Paroxetine had a significant benefit on sleep problems in both depressed and non-depressed cancer patients. However, rates of sleep problems remained high even among those effectively treated for depression with paroxetine. There is a need to develop and deliver sleep-specific interventions to effectively treat sleep-related side effects of cancer treatments. These findings suggest that sleep problems and depression are prevalent and co-morbid. Cancer progression, its response to treatment, and overall patient survival are intricately linked to host factors, such as inflammatory response and circadian rhythms, including sleep/wake cycles. Sleep problems and depression are modifiable host factors that can influence inflammation and impact cancer progression and quality of life. Future research should focus on discovering the pathogenesis of sleep dysregulation and depression in cancer so that better treatment approaches can be developed to ameliorate these symptoms.
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http://dx.doi.org/10.1016/j.sleep.2012.06.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3664933PMC
October 2012