Publications by authors named "Abdoulaye Karaboué"

21 Publications

  • Page 1 of 1

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

Undetectable -Mutant Clones in Plasma: Possible Implication for Anti-EGFR Therapy and Prognosis in Patients With -Mutant Metastatic Colorectal Cancer.

JCO Precis Oncol 2020 16;4. Epub 2020 Sep 16.

Oncogenetics Department, Assistance Publique-Hôpitaux de Paris, Paul Brousse Hospital, Université Paris-Saclay, Villejuif, France.

Purpose: Combining cetuximab with chemotherapy provides clinical benefit to 60% of the patients with wild-type (-wt) metastatic colorectal cancer (mCRC). This pilot study investigated the efficacy of cetuximab-based chemotherapy in a sample of patients (40%) with mutation (-mt) in their primary tumor whose circulating tumor DNA (ctDNA) was -wt.

Materials And Methods: The occurrence of Kirsten rat sarcoma viral oncogene homolog (), neuroblastoma rat sarcoma viral oncogene homolog (NRAS), V-raf murine sarcoma viral oncogene homolog B1 (), and mutations was determined in ctDNA by using a new ultrasensitive analysis based on mass spectrometry detection. All consenting patients with confirmed -mt mCRC had disease progression on previous chemotherapy that contained no anti-epidermal growth factor receptor (EGFR). The patients with -wt ctDNA received cetuximab + fluorouracil, leucovorin, and irinotecan (FOLFIRI), whereas those with -mt ctDNA were treated with the oncologist's choice of therapy.

Results: Of 16 registered patients, 11 were male and five female. They were age 48 to 81 years, and they had unresectable metastatic adenocarcinoma from the colon (n = 11) or rectum (n = 5), with a median of two metastatic sites. They had received a median number of three previous chemotherapy protocols. Plasma genotyping identified -mt in seven patients (44%) and -wt in nine patients (56%). In the patients with wt ctDNA, objective tumor response rate was 50.0%, including one complete response and four partial responses after a median number of 6 courses of cetuximab + FOLFIRI (range, 1 to 16 courses). Two of the nine patients had stable disease, and two had progressive disease. No grade 3 to 4 toxicities were encountered. One-year survival rates were 60.0% for the patients with -wt ctDNA and 17.9% for those with -mt ctDNA. Median overall survival times were not reached and 4.7 months, respectively.

Conclusion: Patients with -mt mCRC whose plasma biopsies contained -wt could benefit from cetuximab-based therapy, a hypothesis to be tested in a prospective randomized trial.
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http://dx.doi.org/10.1200/PO.19.00400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529530PMC
September 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

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

Patient-tailored FOLFIRINOX as first line treatment of patients with advanced pancreatic adenocarcinoma.

Medicine (Baltimore) 2019 Apr;98(16):e15341

Assistance Publique-Hôpitaux de Paris, Department of Medical Oncology, Paul Brousse Hospital.

FOLFIRINOX is one of the most effective reference regimens in the 1st line treatment of locally advanced (LA) and metastatic pancreatic cancer (mPC), despite its high toxicity. We evaluated our real-life experience with "patient-tailored intent to treat FOLFIRINOX" in patients with LA or mPC compared to other reports along with the pivotal phase III trial.We analyzed data from all consecutive patients with pancreatic ductal adenocarcinoma treated with dose-modified FOLFIRINOX in 2016 at Paul Brousse University Hospital. Irinotecan was administered whenever initial serum bilirubin was <1.5 × upper limit of normal. Oxaliplatin was stopped for severe sensory neuropathy. Initial dose reductions were made according to patient profile (eg, age, comorbidities) and later due to toxicity. The treatment was continued until surgery or disease progression. Endpoints were time to progression (TTP), overall survival (OS), objective response rate (ORR), and secondary complete resection (R0R1).Thirty-seven patients with unresectable LA or mPC received patient-tailored FOLFIRINOX as 1st line chemotherapy. There were 22 male (59%) and 15 female patients (41%) aged 44 to 81 years with LA (18 patients, 49%) and mPC (19 patients, 51%). They had World Health Organization-performance status of 0 (59%) or 1 (41%). A total of 384 cycles were administered. Median dose intensities (mg/m/w) were 28.9 for oxaliplatin, 56.8 for irinotecan, and 886.2 for 5-fluorouracil. Thirty-four patients were assessed for response; ORR and disease control rates were 47% and 85%, respectively. R0R1 rate was 30%. Median TTP and OS were 9.6 and 14.6 months. LA disease was associated with significantly longer TTP and OS (P < .001).FOLFIRINOX with patient-tailored dose adaptations seems to offer better results in patients with advanced PC. This approach in the neoadjuvant setting results in a macroscopic R0R1 in 61% of patients with initially unresectable disease. It deserves prospective evaluation to further improve outcomes in the management of advanced PC.
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http://dx.doi.org/10.1097/MD.0000000000015341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6494255PMC
April 2019

Home-Based e-Health Platform for Multidimensional Telemonitoring of Symptoms, Body Weight, Sleep, and Circadian Activity: Relevance for Chronomodulated Administration of Irinotecan, Fluorouracil-Leucovorin, and Oxaliplatin at Home-Results From a Pilot Study.

JCO Clin Cancer Inform 2018 12;2:1-15

Pasquale Innominato, North Wales Cancer Centre, Betsi Cadwaladr University Health Board, Denbighshire; Pasquale Innominato, Sandra Komarzynski, and Francis Lévi, Warwick Medical School, Coventry, United Kingdom; Pasquale Innominato, Sandra Komarzynski, Ayhan Ulusakarya, Mohamed Bouchahda, and Francis Lévi, Institut National de la Santé et de la Recherche Médicale, Unit 935; Ayhan Ulusakarya, Mohamed Bouchahda, Mazen Haydar, Rachel Bossevot-Desmaris, Magali Mocquery, Virginie Plessis, and Francis Lévi, Assistance Publique-Hôpitaux de Paris, Paul Brousse Hospital, Villejuif; and Abdoulaye Karaboué, AK-SCIENCE, Research and Therapeutic Innovation, Vitry-sur-Seine, France.

Purpose: To assess the impact of chronomodulated irinotecan fluorouracil-leucovorin and oxaliplatin (chronoIFLO4) delivered at home on the daily life of patients with cancer in real time using a home-based e-Health multifunction and multiuser platform. This involved multidimensional telemonitoring of circadian rest-activity rhythm (CircAct), sleep, patient-reported outcome measures, and body weight changes (BWCs).

Patients And Methods: Patients received chronoIFLO4 fortnightly at home. Patients completed the 19-item MD Anderson Symptom Inventory on an interactive electronic screen, weighed themselves on a dedicated scale, and continuously wore a wrist accelerometer for CircAct and sleep monitoring. Daily data were securely teletransmitted to a specific server accessible by the hospital team. The clinically relevant CircAct parameter dichotomy index I < O and sleep efficiency (SE) were calculated. The dynamic patterns over time of patient-reported outcome measures, BWC, I < O, and SE informed the oncology team on tolerance in real time.

Results: The platform was installed in the home of 11 patients (48 to 72 years of age; 45% men; 27% with performance status = 0), who were instructed on its use on site. They received 26 cycles and provided 5,891 data points of 8,736 expected (67.4%). The most severe MD Anderson Symptom Inventory scores were: interference with work (mean: 5.1 of 10) or general activity (4.9), fatigue (4.9), distress (4.2), and appetite loss (3.6). Mean BWC was -0.9%, and mean SE remained > 82%. CircAct disruption (I < O ≤ 97.5%) was observed in four (15%) cycles before chronoIFLO4 start and in five (19%) cycles at day 14.

Conclusion: The patient-centered multidimensional telemonitoring solution implemented here was well accepted by patients receiving multidrug chemotherapy at home. Moreover, it demonstrated that chronoIFLO4 was a safe therapeutic option. Such integrated technology allows the design of innovative management approaches, ultimately improving patients' experience with chemotherapy, wellbeing, and outcomes.
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http://dx.doi.org/10.1200/CCI.17.00125DOI Listing
December 2018

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

Pharmacogenetic determinants of outcomes on triplet hepatic artery infusion and intravenous cetuximab for liver metastases from colorectal cancer (European trial OPTILIV, NCT00852228).

Br J Cancer 2017 Sep 17;117(7):965-973. Epub 2017 Aug 17.

INSERM, UMRS 935 Team 'Cancer Chronotherapy and Postoperative Liver Function', Campus CNRS, 7 rue Guy Môquet, and UMRS 1193 'Physiopathology and treatment of Liver diseases', Paul Brousse Hospital, 14 avenue Paul-Vaillant-Couturier, 94800 Villejuif, France.

Background: The hepatic artery infusion (HAI) of irinotecan, oxaliplatin and 5-fluorouracil with intravenous cetuximab achieved outstanding efficacy in previously treated patients with initially unresectable liver metastases from colorectal cancer. This planned study aimed at the identification of pharmacogenetic predictors of outcomes.

Methods: Circulating mononuclear cells were analysed for 207 single-nucleotide polymorphisms (SNPs) from 34 pharmacology genes. Single-nucleotide polymorphisms passing stringent Hardy-Weinberg equilibrium test were tested for their association with outcomes in 52 patients (male/female, 36/16; WHO PS, 0-1).

Results: VKORC1 SNPs (rs9923231 and rs9934438) were associated with early and objective responses, and survival. For rs9923231, T/T achieved more early responses than C/T (50% vs 5%, P=0.029) and greatest 4-year survival (46% vs 0%, P=0.006). N-acetyltransferase-2 (rs1041983 and rs1801280) were associated with up to seven-fold more macroscopically complete hepatectomies. Progression-free survival was largest in ABCB1 rs1045642 T/T (P=0.026) and rs2032582 T/T (P=0.035). Associations were found between toxicities and gene variants (P<0.05), including neutropenia with ABCB1 (rs1045642) and SLC0B3 (rs4149117 and rs7311358); and diarrhoea with CYP2C9 (rs1057910), CYP2C19 (rs3758581), UGT1A6 (rs4124874) and SLC22A1 (rs72552763).

Conclusion: VKORC1, NAT2 and ABCB1 variants predicted for HAI efficacy. Pharmacogenetics could guide the personalisation of liver-targeted medico-surgical therapies.
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http://dx.doi.org/10.1038/bjc.2017.278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625679PMC
September 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

Early tumour response as a survival predictor in previously- treated patients receiving triplet hepatic artery infusion and intravenous cetuximab for unresectable liver metastases from wild-type KRAS colorectal cancer.

Eur J Cancer 2016 11 18;68:163-172. Epub 2016 Oct 18.

AP-HP, Departments of Medical Oncology, Hepato-Biliary Surgery and Radiology, Paul Brousse Hospital, Villejuif, France; INSERM and Paris-Saclay UMR S935, CNRS Campus, Villejuif, France; Cancer Chronotherapy Unit, Warwick Medical School, Coventry, United Kingdom. Electronic address:

Background: Early tumour shrinkage has been associated with improved survival in patients receiving cetuximab-based systemic chemotherapy for liver metastases from colorectal cancer (LM-CRC). We tested this hypothesis for previously treated LM-CRC patients receiving cetuximab (500 mg/m) and triplet hepatic artery infusion (HAI) within European trial OPTILIV.

Methods: Irinotecan (180 mg/m), 5-fluorouracil (2800 mg/m) and oxaliplatin (85 mg/m) were given as chronomodulated or conventional delivery. Patients were retrospectively categorised as early responders (complete or partial RECIST response after three courses) or non-early responders (late or no response). Prognostic factors were determined using multivariate logistic or Cox regression models.

Results: Response was assessed in 57 of 64 registered patients (89%), who had previously received one to three prior systemic chemotherapy protocols. An early response occurred at 6 weeks in 16 patients (28%; 9 men, 7 women), aged 33-76 years, with a median of 12 liver metastases (LMs) (2-50), involving five segments (1-8). Ten patients had a late response, and 31 patients had no response. Grade 3-4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulation-odds ratio (OR): 6.0 (1.2-29.8; p = 0.029)-and LM diameter ≤57 mm-OR: 5.3 (1.1-25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resection-OR: 11.8 (1.4-100.2; p = 0.024) and overall survival-hazard ratio: 0.39 (0.17-0.88; p = 0.023) in multivariate analyses.

Conclusions: Early tumour response on triplet HAI and systemic cetuximab predicted for complete macroscopic liver resection and prolonged survival for LM-CRC patients within a multicenter conversion-to-resection medicosurgical strategy. Confirmation is warranted for early response on HAI to guide decision making. Protocol numbers: EUDRACT 2007-004632-24 NCT00852228.
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http://dx.doi.org/10.1016/j.ejca.2016.09.011DOI Listing
November 2016

Pharmacokinetics of Irinotecan, Oxaliplatin and 5-Fluorouracil During Hepatic Artery Chronomodulated Infusion: A Translational European OPTILIV Study.

Clin Pharmacokinet 2017 02;56(2):165-177

Institut Claudius-Regaud, CRCT, Université de Toulouse, Inserm, UPS, Toulouse, France.

The combination of hepatic artery infusion (HAI) of irinotecan, 5-fluorouracil and oxaliplatin with intravenous cetuximab has safely achieved prolonged survival in colorectal cancer patients with extensive liver metastases and prior treatment. Systemic exposure to the drugs or their main metabolites was determined during the first course of chronomodulated triplet HAI in 11 patients and related to toxicities after one or three courses. Consistent trends were found between the area under the plasma concentration-time curve (AUC) values of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN38; a bioactive metabolite), total oxaliplatin and platinum ultrafiltrate (P-UF), on the one hand, and subsequent leukopenia severity, on the other hand. Moreover, the maximum plasma concentration (C ) and the AUC of P-UF significantly predicted grades of diarrhoea (p = 0.004 and 0.017, respectively) and anaemia (p = 0.001 and 0.008, respectively) after the first course. Systemic drug exposure helps explain both the adverse events and the low rate of extrahepatic progression-a usual drawback of HAI chemotherapy-thus supporting upfront testing of the regimen. Systems optimization of chronomodulated HAI delivery could further reduce adverse events.
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http://dx.doi.org/10.1007/s40262-016-0431-2DOI Listing
February 2017

Wrist actimetry circadian rhythm as a robust predictor of colorectal cancer patients survival.

Chronobiol Int 2014 Oct 13;31(8):891-900. Epub 2014 Jun 13.

Biological Rhythms and Cancers, INSERM, UMRS , Villejuif Cedex , France .

The disruption of the circadian timing system (CTS), which rhythmically controls cellular metabolism and proliferation, accelerated experimental cancer progression. A measure of CTS function in cancer patients could thus provide novel prediction information for outcomes, and help to identify novel specific therapies. The rest-activity circadian rhythm is a reliable and non-invasive CTS biomarker, which was monitored using a wrist watch accelerometer for 2 days in 436 patients with metastatic colorectal cancer. The relative percentage of activity in-bed versus out-of-bed (I < O) constituted the tested CTS measure, whose prognostic value for overall survival (OS) and progression-free survival (PFS) was determined in a pooled analysis of three patient cohorts with different treatment exposures. Median OS was 21.6 months [17.8-25.5] for patients with I < O above the median value of 97.5% as compared to 11.9 months [10.4-13.3] for those with a lower I < O (Log-rank p < 0.001). Multivariate analyses retained continuous I < O as a joint predictor of both OS and PFS, with respective hazard ratios (HR) of 0.954 (p < 0.001) and 0.970 (p < 0.001) for each 1% increase in I < O. HRs had similar values in all the patient subgroups tested. The circadian physiology biomarker I < O constitutes a robust and independent quantitative predictor of cancer patient outcomes, that can be easily and cost-effectively measured during daily living. Interventional studies involving 24-h schedules of clock-targeted drugs, light intensity, exercise and/or meals are needed for testing the relevance of circadian synchronization for the survival of patients with disrupted rhythms.
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http://dx.doi.org/10.3109/07420528.2014.924523DOI Listing
October 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

Thoracic surface temperature rhythms as circadian biomarkers for cancer chronotherapy.

Chronobiol Int 2014 Apr 7;31(3):409-20. Epub 2014 Jan 7.

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

The disruption of the temperature circadian rhythm has been associated with cancer progression, while its amplification resulted in cancer inhibition in experimental tumor models. The current study investigated the relevance of skin surface temperature rhythms as biomarkers of the Circadian Timing System (CTS) in order to optimize chronotherapy timing in individual cancer patients. Baseline skin surface temperature at four sites and wrist accelerations were measured every minute for 4 days in 16 patients with metastatic gastro-intestinal cancer before chronotherapy administration. Temperature and rest-activity were recorded, respectively, with wireless skin surface temperature patches (Respironics, Phillips) and an actigraph (Ambulatory Monitoring). Both variables were further monitored in 10 of these patients during and after a 4-day course of a fixed chronotherapy protocol. Collected at baseline, during and after therapy longitudinal data sets were processed using Fast Fourier Transform Cosinor and Linear Discriminant Analyses methods. A circadian rhythm was statistically validated with a period of 24 h (p < 0.05) for 49/61 temperature time series (80.3%), and 15/16 rest-activity patterns (93.7%) at baseline. However, individual circadian amplitudes varied from 0.04 °C to 2.86 °C for skin surface temperature (median, 0.72 °C), and from 16.6 to 146.1 acc/min for rest-activity (median, 88.9 acc/min). Thirty-nine pairs of baseline temperature and rest-activity time series (75%) were correlated (r > |0.7|; p < 0.05). Individual circadian acrophases at baseline were scattered from 15:18 to 6:05 for skin surface temperature, and from 12:19 to 15:18 for rest-activity, with respective median values of 01:10 (25-75% quartiles, 22:35-3:07) and 14:12 (13:14-14:31). The circadian patterns in skin surface temperature and rest-activity persisted or were amplified during and after fixed chronotherapy delivery for 5/10 patients. In contrast, transient or sustained disruption of these biomarkers was found for the five other patients, as indicated by the lack of any statistically significant dominant period in the circadian range. No consistent correlation (r < |0.7|, p ≥ 0.05) was found between paired rest-activity and temperature time series during fixed chronotherapy delivery. In conclusion, large inter-patient differences in circadian amplitudes and acrophases of skin surface temperature were demonstrated for the first time in cancer patients, despite rather similar rest-activity acrophases. The patient-dependent coupling between both CTS biomarkers, and its possible alteration on a fixed chronotherapy protocol, support the concept of personalized cancer chronotherapy.
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http://dx.doi.org/10.3109/07420528.2013.864301DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4221267PMC
April 2014

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

Prediction of survival by neutropenia according to delivery schedule of oxaliplatin-5-Fluorouracil-leucovorin for metastatic colorectal cancer in a randomized international trial (EORTC 05963).

Chronobiol Int 2011 Aug;28(7):586-600

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

Circadian clocks control cellular proliferation and drug metabolism over the 24 h. However, circadian chronomodulated chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (chronoFLO4) offered no survival benefit as compared with the non-time-stipulated FOLFOX2, in an international randomized trial involving patients with previously untreated metastatic colorectal cancer (EORTC 05963). The authors hypothesized that treatment near maximum tolerated dose could disrupt circadian clocks thus impairing the efficacy of chronoFLO4 but not of FOLFOX2. Patients with available data (N = 556) were categorized into three subgroups according to the worst grade (G) of neutropenia experienced during treatment. Distinct multivariate models with time-dependent covariates were constructed for each treatment schedule. Neutropenia incidence (all grades) was 33% on chronoFLO4 and 61% on FOLFOX2 (p < .0001), and G3-4 were 7% and 25%, respectively (p < .0001). Neutropenia was significantly more frequent in women than men on either schedule (FOLFOX2, p = .003; chronoFLO4, p = .04). Median survival was 20.7 mo in patients with G3-4 neutropenia versus 12.5 mo in neutropenia-free patients on FOLFOX2 (p < .0001). Corresponding figures were 13.7 and 19.4 mo, respectively, on chronoFLO4 (p = .36). Multivariate analysis confirmed occurrence of severe neutropenia independently predicted for better overall survival on FOLFOX2 (HR = 0.56; p = .015), and worse survival on chronoFLO4 (HR = 1.77, p = .06), with a significant interaction test (p < .0001). Prediction of better survival in neutropenic patients on FOLFOX2 supports the administration of conventional chemotherapy near maximum tolerated dose. The opposite trend shown here for chronoFLO4 supports the novel concept of jointly optimized hematologic tolerability and efficacy through personalized circadian-timed therapy.
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http://dx.doi.org/10.3109/07420528.2011.597532DOI Listing
August 2011

Skin surface temperature rhythms as potential circadian biomarkers for personalized chronotherapeutics in cancer patients.

Interface Focus 2011 Feb;1:48-60

Biomedical Engineering and Physical Science, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MD, USA.

Chronotherapeutics involve the administration of treatments according to circadian rhythms. Circadian timing of anti-cancer medications has been shown to improve treatment tolerability up to fivefold and double efficacy in experimental and clinical studies. However, the physiological and the molecular components of the circadian timing system (CTS), as well as gender, critically affect the success of a standardized chronotherapeutic schedule. In addition, a wrongly timed therapy or an excessive drug dose disrupts the CTS. Therefore, a non-invasive approach to accurately detect and monitor circadian rhythms is needed for a dynamic assessment of the CTS in order to personalize chronomodulated drug delivery schedule in cancer patients. Since core body temperature is a robust circadian biomarker, we recorded temperature at multiple locations on the skin of the upper chest and back of controls and cancer patients continuously. Variability in the circadian phase existed among patch locations in individual subjects over the course of 2-6 days, demonstrating the need to monitor multiple skin temperature locations to determine the precise circadian phase. Additionally, we observed that locations identified by infrared imaging as relatively cool had the largest 24 h temperature variations. Disruptions in skin temperature rhythms during treatment were found, pointing to the need to continually assess circadian timing and personalize chronotherapeutic schedules.
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http://dx.doi.org/10.1098/rsfs.2010.0012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085452PMC
February 2011

Cetuximab and circadian chronomodulated chemotherapy as salvage treatment for metastatic colorectal cancer (mCRC): safety, efficacy and improved secondary surgical resectability.

Cancer Chemother Pharmacol 2011 Feb 17;67(2):339-48. Epub 2010 Apr 17.

INSERM, U776 Rythmes biologiques et cancers, Hôpital Paul Brousse, 14 avenue Paul-Vaillant-Couturier, 94807 Villejuif Cedex, France.

Background: Circadian rhythm disruption was linked to high serum levels of Transforming Growth Factor Receptor α, an Epidermal Growth Factor Receptor (EGFR) ligand and poor survival in patients with metastatic colorectal cancer (mCRC). We hypothesized that EGFR blockade with cetuximab would enhance the activity of chronotherapy as a result of improved circadian coordination.

Methods: All the patients with mCRC referred to our unit for progression on prior chemotherapy over a 30-month-period received weekly cetuximab and fortnightly chronotherapy.

Results: Fifty-six patients were treated with a median of six courses of fluoropyrimidine-based chemotherapy and irinotecan (61%), oxaliplatin (25%) or both (14%) after a median of three prior regimens. We found no EFGR amplification by FISH in the tumor of 27 consecutive patients. Acneiform rash and diarrhea were the most common toxicities. Objective response rate was 32.1% and positively correlated with rash grade (p = 0.025). None of the responders had K-Ras mutation in their tumor. Median progression-free and overall survival were 4.6 and 13.7 months, respectively. Complete macroscopic resections of metastases in liver, lung or other abdominopelvic sites were performed following tumor downstaging by the treatment regimen in 11 patients (21%), 8 of whom being alive at 3 years. These figures are twice as high as those reported for first-line combination of cetuximab with conventional chemotherapy or for third line chronotherapy.

Conclusions: The addition of cetuximab to chronotherapy allowed safe and effective therapeutic control of metastases, including their complete resection, despite previous failure of several treatment regimens.
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http://dx.doi.org/10.1007/s00280-010-1327-8DOI Listing
February 2011

Acquired KRAS mutations during progression of colorectal cancer metastases: possible implications for therapy and prognosis.

Cancer Chemother Pharmacol 2010 Aug 2;66(3):605-9. Epub 2010 Apr 2.

Chronotherapy Unit and Department of Medical Oncology, Assistance Publique-Hôpitaux de Paris, Villejuif, France.

Purpose: Documentation of a wild-type (wt) KRAS gene in tumor has become mandatory for the prescription of anti-EGFR monoclonal antibodies in patients with colorectal cancer (CRC). Acquired KRAS mutations have seldom been reported in metastases from wt KRAS primary CRC. We report the first case of multiple KRAS mutations acquired during the metastatic phase of CRC, and retrospectively reviewed all patients with CRC, in whom KRAS was analyzed in at least two tumor samples from distinct lesions.

Methods: Genomic DNA purified from paraffin-embedded tissues was used after histological quantification of tumor tissue. The seven KRAS mutations located within codons 12 and 13 were screened using the allelic discrimination assay.

Results: A 35-year-old woman with CRC liver metastasis, resistant to all conventional cytotoxic agents, experienced for the first time significant tumor shrinkage while cetuximab was added, allowing hepatic resection. Further liver relapse occurred on cetuximab, but a new hepatic resection was attempted. No mutation in KRAS was detected in the primary colon tumor or in synchronous liver metastases. In contrast, in metachronous liver metastasis samples, two distinct mutations at codon 13 and 12 were detected. No acquired mutations were found in all the other 12 CRC cases with at least two serially performed KRAS analyses.

Conclusions: Our findings suggest that late switch in KRAS mutational status could occur more frequently than currently recognized and account for acquired resistance to anti-EGFR therapies. Prospective studies are warranted to better estimate the incidence of change in KRAS mutational status and assess their clinical relevance.
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http://dx.doi.org/10.1007/s00280-010-1298-9DOI Listing
August 2010

Implications of circadian clocks for the rhythmic delivery of cancer therapeutics.

Adv Drug Deliv Rev 2007 Aug 4;59(9-10):1015-35. Epub 2007 Jul 4.

INSERM, U776 Rythmes biologiques et cancers, Hôpital Paul Brousse, Villejuif, F-94807, France.

The circadian timing system controls drug metabolism and cellular proliferation over the 24 h through molecular clocks in each cell, circadian physiology, and the suprachiasmatic nuclei--a hypothalamic pacemaker clock that coordinates circadian rhythms. As a result, both the toxicity and efficacy of over 30 anticancer agents vary by more than 50% as a function of dosing time in experimental models. The circadian timing system also down-regulates malignant growth in experimental models and possibly in cancer patients. Programmable-in-time infusion pumps and rhythmic physiology monitoring devices have made possible the application of chronotherapeutics to more than 2000 cancer patients without hospitalization. This strategy first revealed the antitumor efficacy of oxaliplatin against colorectal cancer. In this disease, international clinical trials have shown a five-fold improvement in patient tolerability and near doubling of antitumor activity through the chronomodulated, in comparison to constant-rate, delivery of oxaliplatin and 5-fluorouracil-leucovorin. Here, the relevance of the peak time, with reference to circadian rhythms, of the chemotherapeutic delivery of these cancer medications for achieving best tolerability was investigated in 114 patients with metastatic colorectal cancer and in 45 patients with non-small cell lung cancer. The incidence of severe adverse events varied up to five-fold as a function of the choice of when during the 24 h the peak dose of the medications was timed. The optimal chronomodulated schedules corresponded to peak delivery rates at 1 a.m. or 4 a.m. for 5-fluorouracil-leucovorin, at 1 p.m. or 4 p.m. for oxaliplatin, and at 4 p.m. for carboplatin. Sex of patient was an important determinant of drug schedule tolerability. This finding is consistent with recent results from a chronotherapy trial involving 554 patients with metastatic colorectal cancer, where sex also predicted survival outcome from chronotherapy, but not conventional drug delivery. Ongoing translational studies, mathematical modeling, and technology developments are further paving the way for tailoring cancer chronotherapeutics to the main rhythmic characteristics of the individual patient. Targeting therapeutic delivery to the dynamics of the cross-talk between the circadian clock, the cell division cycle, and pharmacology pathways represents a new challenge to concurrently improve the quality of life and survival of cancer patients through personalized cancer chronotherapeutics.
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http://dx.doi.org/10.1016/j.addr.2006.11.001DOI Listing
August 2007