27 research outputs found
Sex-dependent least toxic timing of irinotecan combined with chronomodulated chemotherapy for metastatic colorectal cancer : randomized multicenter
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 fixedâtime chronomodulated FluorouracilâLeucovorinâOxaliplatin for 4 days, q3 weeks. The sexâspecific circadian characteristics of grade (G) 3â4 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 3â4 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 3â4 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
Wrist actimetry circadian rhythm as a robust predictor of colorectal cancer patients survival
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 (Iâ<âO) 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 [17.8â25.5] for patients with Iâ<âO above the median value of 97.5% as compared to 11.9 months [10.4â13.3] for those with a lower Iâ<âO (Log-rank pâ<â0.001). Multivariate analyses retained continuous Iâ<âO as a joint predictor of both OS and PFS, with respective hazard ratios (HR) of 0.954 (pâ<â0.001) and 0.970 (pâ<â0.001) for each 1% increase in Iâ<âO. HRs had similar values in all the patient subgroups tested. The circadian physiology biomarker Iâ<âO 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
Circadian rest-activity rhythm as an objective biomarker of patient-reported outcomes in patients with advanced cancer
Background
Psychosocial symptoms often cluster together, are refractory to treatment, and impair healthârelated quality of life (HRâQoL) 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 restâactivity rhythm provides a reliable and objective estimate of the most frequent patientâreported outcome measures (PROMs).
Methods
Two datasets were used, each involving concomitant 3âday time series of wrist actigraphy and HRâQoL questionnaires: EORTC QLQâC30 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 HRâQoL domains. Fatigue and anorexia were worse in patients with circadian disruption. The differences were both statistically and clinically significant (P < 0.001; d â„ 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 â„ 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 patientsâ HRâQoL and symptoms that deserves therapeutic exploitation
Time-dependent efficacy of checkpoint inhibitor nivolumab : results from a pilot study in patients with metastatic non-small-cell lung cancer
Hypothesis: Prior experimental and human studies have demonstrated the circadian organization of immune cellsâ proliferation, trafficking, and antigen recognition and destruction. Nivolumab targets T(CD8) cells, the functions, and trafficking of which are regulated by circadian clocks, hence suggesting possible daily changes in nivolumabâs efficacy. Worse progression-free survival (PFS), and overall survival (OS) were reported for malignant melanoma patients receiving more than 20% of their immune checkpoint inhibitor infusions after 16:30 as compared to earlier in the day. Methods: Consecutive metastatic non-small-cell cancer (NSCLC) patients received nivolumab (240 mg iv q 2 weeks) at a daily time that was ârandomlyâ allocated for each course on a logistical basis by the day-hospital coordinators. The median time of all nivolumab administrations was computed for each patient. The study population was split into two timing groups based upon the median value of the median treatment times of all patients. CTCAE-toxicity rates, iRECIST-tumor responses, PFS and OS were computed according to nivolumab timing. PFS and OS curves were compared and hazard ratios (HR) were computed for all major categories of characteristics. Multivariable and sensitivity analyses were also performed. Results: The study accrued 95 stage-IV NSCLC patients (PS 0â1, 96%), aged 41â83 years. The majority of nivolumab administrations occurred between 9:27 and 12:54 for 48 patients (âmorningâ group) and between 12:55 and 17:14 for the other 47 (âafternoonâ group). Median PFS (95% CL) was 11.3 months (5.5â17.1) for the âmorningâ group and 3.1 months (1.5â4.6) for the âafternoonâ one (p < 0.001). Median OS was 34.2 months (15.1â53.3) and 9.6 months (4.9â14.4) for the âmorningâ group and the âafternoonâ one, respectively (p < 0.001). Multivariable analyses identified âmorningâ timing as a significant predictor of longer PFS and OS, with respective HR values of 0.26 (0.11â0.58) and 0.17 (0.08â0.37). The timing effect was consistent across all patient subgroups tested. Conclusions: Nivolumab was nearly four times as effective following âmorningâ as compared to âafternoonâ dosing in this cohort of NSCLC patients. Prospective timing-studies are needed to minimize the risk of resistance and to maximize the benefits from immune checkpoint inhibitors
Impact of assessment frequency of patient-reported outcomes : an observational study using an eHealth platform in cancer patients
Background and aim
The evaluation of patient-reported outcomes (PRO) in cancer has proven relevant positive clinical impact on patientsâ 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.,â>â1, 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.,â>â6) 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
Efficacy and safety of chronomodulated irinotecan, oxaliplatin, 5âfluorouracil and leucovorin combination as firstâ or secondâline treatment against metastatic colorectal cancer : results from the International EORTC 05011 Trial
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 circadianâbased administration (chronoIFLO5) as either firstâ or secondâline treatment, within the timeâfinding EORTC 05011 trial. Fiveâday chronoIFLO5 was administered every 3âweeks in patients with PS 0, 1 or 2. It consisted of chronomodulated irinotecan (180âmg/sqm), oxaliplatin (80âmg/sqm) and fluorouracilâleucovorin (2800 and 1200âmg/sqm, respectively). For our study, toxicity and antitumour activity were evaluated separately in firstâ and secondâline settings. Primary endpoints included Grade 3â4 toxicity rates, best objective response rate (ORR), progressionâfree survival (PFS) and overall survival (OS). Oneâhundred fortyânine and 44 patients were treated in firstâline and secondâline settings, respectively, with a total of 1138âcycles with median relative dose intensities of about 90%. Demographics were comparable in the two groups. Thirtyâsix (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: 54.2â70.4] and resulted in median PFS and OS of 8.7 months [7.5â9.9] and 19.9 months [15.4â24.5]. Corresponding figures in second line were 37.5% [22.5â52.5], 6.7 months [4.8â8.9] and 16.3 months [11.8â20.8]. 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
Clinical relevance of the first domomedicine platform securing multidrug chronotherapy delivery in metastatic cancer patients at home : the inCASA European project
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 patientâs 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<O) were computed. Chemotherapy was administered according to the patient medical condition. Compliance was evaluated according to the proportions of (1) patient-days with all data available (full) and (2) patient-days with at least one parameter available (minimal). Acceptability was assessed using the Whole Systems Demonstrator Service User Technology Acceptability Questionnaire. Linear discriminant analysis was used to identify the combination of parameters associated with subsequent unplanned hospitalization.
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<O), body weight change, and MDASI scores predicted for ensuing emergency hospitalization within 3 days, with an accuracy of 94%.
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
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
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/m2) and triplet hepatic artery infusion (HAI) within European trial OPTILIV.
Methods:
Irinotecan (180 mg/m2), 5-fluorouracil (2800 mg/m2) and oxaliplatin (85 mg/m2) 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 33â76 years, with a median of 12 liver metastases (LMs) (2â50), involving five segments (1â8). Ten patients had a late response, and 31 patients had no response. Grade 3â4 fatigue selectively occurred in the non-early responders (0% versus 26%; p = 0.024). Early tumour response was jointly predicted by chronomodulationâodds ratio (OR): 6.0 (1.2â29.8; p = 0.029)âand LM diameter â€57 mmâOR: 5.3 (1.1â25.0; p = 0.033). Early tumour response predicted for both R0-R1 liver resectionâOR: 11.8 (1.4â100.2; p = 0.024) and overall survivalâhazard ratio: 0.39 (0.17â0.88; 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