Why does circadian timing of administration matter for immune checkpoint inhibitors' efficacy?

BACKGROUND: Tolerability and antitumour efficacy of chemotherapy and radiation therapy can vary largely according to their time of administration along the 24-h time scale, due to the moderation of their molecular and cellular mechanisms by circadian rhythms. Recent clinical data have highlighted a striking role of dosing time for cancer immunotherapy, thus calling for a critical evaluation. METHODS: Here, we review the clinical data and we analyse the mechanisms through which circadian rhythms can influence outcomes on ICI therapies. We examine how circadian rhythm disorders can affect tumour immune microenvironment, as a main mechanism linking the circadian clock to the 24-h cycles in ICIs antitumour efficacy. RESULTS: Real-life data from 18 retrospective studies have revealed that early time-of-day (ToD) infusion of immune checkpoint inhibitors (ICIs) could enhance progression-free and/or overall survival up to fourfold compared to late ToD dosing. The studies involved a total of 3250 patients with metastatic melanoma, lung, kidney, bladder, oesophageal, stomach or liver cancer from 9 countries. Such large and consistent differences in ToD effects on outcomes could only result from a previously ignored robust chronobiological mechanism. The circadian timing system coordinates cellular, tissue and whole-body physiology along the 24-h timescale. Circadian rhythms are generated at the cellular level by a molecular clock system that involves 15 specific clock genes. The disruption of circadian rhythms can trigger or accelerate carcinogenesis, and contribute to cancer treatment failure, possibly through tumour immune evasion resulting from immunosuppressive tumour microenvironment. CONCLUSIONS AND PERSPECTIVE: Such emerging understanding of circadian rhythms regulation of antitumour immunity now calls for randomised clinical trials of ICIs timing to establish recommendations for personalised chrono-immunotherapies with current and forthcoming drugs.

Digital Remote Monitoring Using an mHealth Solution for Survivors of Cancer: Protocol for a Pilot Observational Study.

BACKGROUND: Healthy lifestyle interventions have a positive impact on multiple disease trajectories, including cancer-related outcomes. Specifically, appropriate habitual physical activity, adequate sleep, and a regular wholesome diet are of paramount importance for the wellness and supportive care of survivors of cancer. Mobile health (mHealth) apps have the potential to support novel tailored lifestyle interventions. OBJECTIVE: This observational pilot study aims to assess the feasibility of mHealth multidimensional longitudinal monitoring in survivors of cancer. The primary objective is to test the compliance (user engagement) with the monitoring solution. Secondary objectives include recording clinically relevant subjective and objective measures collected through the digital solution. METHODS: This is a monocentric pilot study taking place in Bangor, Wales, United Kingdom. We plan to enroll up to 100 adult survivors of cancer not receiving toxic anticancer treatment, who will provide self-reported behavioral data recorded via a dedicated app and validated questionnaires and objective data automatically collected by a paired smartwatch over 16 weeks. The participants will continue with their normal routine surveillance care for their cancer. The primary end point is feasibility (eg, mHealth monitoring acceptability). Composite secondary end points include clinically relevant patient-reported outcome measures (eg, the Edmonton Symptom Assessment System score) and objective physiological measures (eg, step counts). This trial received a favorable ethical review in May 2023 (Integrated Research Application System 301068). RESULTS: This study is part of an array of pilots within a European Union funded project, entitled "GATEKEEPER," conducted at different sites across Europe and covering various chronic diseases. Study accrual is anticipated to commence in January 2024 and continue until June 2024. It is hypothesized that mHealth monitoring will be feasible in survivors of cancer; specifically, at least 50% (50/100) of the participants will engage with the app at least once a week in 8 of the 16 study weeks. CONCLUSIONS: In a population with potentially complex clinical needs, this pilot study will test the feasibility of multidimensional remote monitoring of patient-reported outcomes and physiological parameters. Satisfactory compliance with the use of the app and smartwatch, whether confirmed or infirmed through this study, will be propaedeutic to the development of innovative mHealth interventions in survivors of cancer. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/52957.

Impact of immunotherapy time-of-day infusion on survival and immunologic correlates in patients with metastatic renal cell carcinoma: a multicenter cohort analysis.

BACKGROUND: Recent studies have demonstrated that earlier time-of-day infusion of immune checkpoint inhibitors (ICIs) is associated with longer progression-free survival (PFS) and overall survival (OS) among patients with metastatic melanoma and non-small cell lung cancer. These data are in line with growing preclinical evidence that the adaptive immune response may be more effectively stimulated earlier in the day. We sought to determine the impact of time-of-day ICI infusions on outcomes among patients with metastatic renal cell carcinoma (mRCC). METHODS: The treatment records of all patients with stage IV RCC who began ICI therapy within a multicenter academic hospital system between 2015 and 2020 were reviewed. The associations between the proportion of ICI infusions administered prior to noon (denoting morning infusions) and PFS and OS were evaluated using univariate and multivariable Cox proportional hazards regression. RESULTS: In this study, 201 patients with mRCC (28% women) received ICIs and were followed over a median of 18 months (IQR 5-30). The median age at the time of ICI initiation was 63 years (IQR 56-70). 101 patients (50%) received ≥20% of their ICI infusions prior to noon (Group A) and 100 patients (50%) received <20% of infusions prior to noon (Group B). Across the two comparison groups, initial ICI agents consisted of nivolumab (58%), nivolumab plus ipilimumab (34%), and pembrolizumab (8%). On univariate analysis, patients in Group A had longer PFS and OS compared with those in Group B (PFS HR 0.67, 95% CI 0.48 to 0.94, Punivar=0.020; OS HR 0.57, 95% CI 0.34 to 0.95, Punivar=0.033). These significant findings persisted following multivariable adjustment for age, sex, performance status, International Metastatic RCC Database Consortium risk score, pretreatment lactate dehydrogenase, histology, and presence of bone, brain, and liver metastases (PFS HR 0.70, 95% CI 0.50 to 0.98, Pmultivar=0.040; OS HR 0.57, 95% CI 0.33 to 0.98, Pmultivar=0.043). CONCLUSIONS: Patients with mRCC may benefit from earlier time-of-day receipt of ICIs. Our findings are consistent with established mechanisms of chrono-immunology, as well as with preceding analogous studies in melanoma and lung cancer. Additional prospective randomized trials are warranted.

Circadian Regulation of Drug Responses: Toward Sex-Specific and Personalized Chronotherapy.

Today's challenge for precision medicine involves the integration of the impact of molecular clocks on drug pharmacokinetics, toxicity, and efficacy toward personalized chronotherapy. Meaningful improvements of tolerability and/or efficacy of medications through proper administration timing have been confirmed over the past decade for immunotherapy and chemotherapy against cancer, as well as for commonly used pharmacological agents in cardiovascular, metabolic, inflammatory, and neurological conditions. Experimental and human studies have recently revealed sexually dimorphic circadian drug responses. Dedicated randomized clinical trials should now aim to issue personalized circadian timing recommendations for daily medical practice, integrating innovative technologies for remote longitudinal monitoring of circadian metrics, statistical prediction of molecular clock function from single-timepoint biopsies, and multiscale biorhythmic mathematical modelling. Importantly, chronofit patients with a robust circadian function, who would benefit most from personalized chronotherapy, need to be identified. Conversely, nonchronofit patients could benefit from the emerging pharmacological class of chronobiotics targeting the circadian clock.

Circadian lifestyle determinants of immune checkpoint inhibitor efficacy.

Immune Checkpoint Inhibitors (ICI) have revolutionised cancer care in recent years. Despite a global improvement in the efficacy and tolerability of systemic anticancer treatments, a sizeable proportion of patients still do not benefit maximally from ICI. Extensive research has been undertaken to reveal the immune- and cancer-related mechanisms underlying resistance and response to ICI, yet more limited investigations have explored potentially modifiable lifestyle host factors and their impact on ICI efficacy and tolerability. Moreover, multiple trials have reported a marked and coherent effect of time-of-day ICI administration and patients' outcomes. The biological circadian clock indeed temporally controls multiple aspects of the immune system, both directly and through mediation of timing of lifestyle actions, including food intake, physical exercise, exposure to bright light and sleep. These factors potentially modulate the immune response also through the microbiome, emerging as an important mediator of a patient's immune system. Thus, this review will look at critically amalgamating the existing clinical and experimental evidence to postulate how modifiable lifestyle factors could be used to improve the outcomes of cancer patients on immunotherapy through appropriate and individualised entrainment of the circadian timing system and temporal orchestration of the immune system functions.

GATEKEEPER's Strategy for the Multinational Large-Scale Piloting of an eHealth Platform: Tutorial on How to Identify Relevant Settings and Use Cases.

BACKGROUND: The World Health Organization's strategy toward healthy aging fosters person-centered integrated care sustained by eHealth systems. However, there is a need for standardized frameworks or platforms accommodating and interconnecting multiple of these systems while ensuring secure, relevant, fair, trust-based data sharing and use. The H2020 project GATEKEEPER aims to implement and test an open-source, European, standard-based, interoperable, and secure framework serving broad populations of aging citizens with heterogeneous health needs. OBJECTIVE: We aim to describe the rationale for the selection of an optimal group of settings for the multinational large-scale piloting of the GATEKEEPER platform. METHODS: The selection of implementation sites and reference use cases (RUCs) was based on the adoption of a double stratification pyramid reflecting the overall health of target populations and the intensity of proposed interventions; the identification of a principles guiding implementation site selection; and the elaboration of guidelines for RUC selection, ensuring clinical relevance and scientific excellence while covering the whole spectrum of citizen complexities and intervention intensities. RESULTS: Seven European countries were selected, covering Europe's geographical and socioeconomic heterogeneity: Cyprus, Germany, Greece, Italy, Poland, Spain, and the United Kingdom. These were complemented by the following 3 Asian pilots: Hong Kong, Singapore, and Taiwan. Implementation sites consisted of local ecosystems, including health care organizations and partners from industry, civil society, academia, and government, prioritizing the highly rated European Innovation Partnership on Active and Healthy Aging reference sites. RUCs covered the whole spectrum of chronic diseases, citizen complexities, and intervention intensities while privileging clinical relevance and scientific rigor. These included lifestyle-related early detection and interventions, using artificial intelligence-based digital coaches to promote healthy lifestyle and delay the onset or worsening of chronic diseases in healthy citizens; chronic obstructive pulmonary disease and heart failure decompensations management, proposing integrated care management based on advanced wearable monitoring and machine learning (ML) to predict decompensations; management of glycemic status in diabetes mellitus, based on beat to beat monitoring and short-term ML-based prediction of glycemic dynamics; treatment decision support systems for Parkinson disease, continuously monitoring motor and nonmotor complications to trigger enhanced treatment strategies; primary and secondary stroke prevention, using a coaching app and educational simulations with virtual and augmented reality; management of multimorbid older patients or patients with cancer, exploring novel chronic care models based on digital coaching, and advanced monitoring and ML; high blood pressure management, with ML-based predictions based on different intensities of monitoring through self-managed apps; and COVID-19 management, with integrated management tools limiting physical contact among actors. CONCLUSIONS: This paper provides a methodology for selecting adequate settings for the large-scale piloting of eHealth frameworks and exemplifies with the decisions taken in GATEKEEPER the current views of the WHO and European Commission while moving forward toward a European Data Space.

Impact of Preoperative Chemotherapy Features on Patient Outcomes after Hepatectomy for Initially Unresectable Colorectal Cancer Liver Metastases: A LiverMetSurvey Analysis.

Background: Prognostic factors have been extensively reported after resection of colorectal liver metastases (CLM); however, specific analyses of the impact of preoperative systemic anticancer therapy (PO-SACT) features on outcomes is lacking. Methods: For this real-world evidence study, we used prospectively collected data within the international surgical LiverMetSurvey database from all patients with initially-irresectable CLM. The main outcome was Overall Survival (OS) after surgery. Disease-free (DFS) and hepatic-specific relapse-free survival (HS-RFS) were secondary outcomes. PO-SACT features included duration (cumulative number of cycles), choice of the cytotoxic backbone (oxaliplatin- or irinotecan-based), fluoropyrimidine (infusional or oral) and addition or not of targeted monoclonal antibodies (anti-EGFR or anti-VEGF). Results: A total of 2793 patients in the database had received PO-SACT for initially irresectable diseases. Short (<7 or <13 cycles in 1st or 2nd line) PO-SACT duration was independently associated with longer OS (HR: 0.85 p = 0.046), DFS (HR: 0.81; p = 0.016) and HS-RFS (HR: 0.80; p = 0.05). All other PO-SACT features yielded basically comparable results. Conclusions: In this international cohort, provided that PO-SACT allowed conversion to resectability in initially irresectable CLM, surgery performed as soon as technically feasible resulted in the best outcomes. When resection was achieved, our findings indicate that the choice of PO-SACT regimen had a marginal if any, impact on outcomes.

Holistic Needs Assessment of Cancer Survivors-Supporting the Process Through Digital Monitoring of Circadian Physiology.

The year 2022 could represent a significant juncture in the incorporation of mHealth solutions in routine cancer care. With the recent global COVID-19 pandemic leading a surge in both observation- and intervention-based studies predominantly aimed at remote monitoring there has been huge intellectual investment in developing platforms able to provide real time analytics that are readily usable. Another fallout from the pandemic has seen record waiting times and delayed access to cancer therapies leading to exhausting pressures on global healthcare providers. It seems an opportune time to utilize this boom in platforms to offer more efficient "at home" clinical assessments and less "in department" time for patients. Here, we will focus specifically on the role of digital tools around cancer survivorship, a relevant aspect of the cancer journey, particularly benefiting from integrative approaches. Within that context a further concept will be introduced and that is of the likely upsurge in circadian-based interpretation of continuous monitoring and the engendered therapeutic modifications. Chronobiology across the 24-hour span has long been understood to control key bodily aspects and circadian dysregulation plays a significant role in the risk of cancer and also the response to therapy and therefore progressive outcome. The rapid improvement in minimally invasive monitoring devices is, in the opinion of the authors, likely to advance introducing chronobiological amendments to routine clinical practices with positive impact on cancer survivors.

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 cells' 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 nivolumab's 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 'randomly' 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 0-1, 96%), aged 41-83 years. The majority of nivolumab administrations occurred between 9:27 and 12:54 for 48 patients ('morning' group) and between 12:55 and 17:14 for the other 47 ('afternoon' group). Median PFS (95% CL) was 11.3 months (5.5-17.1) for the 'morning' group and 3.1 months (1.5-4.6) for the 'afternoon' one (p < 0.001). Median OS was 34.2 months (15.1-53.3) and 9.6 months (4.9-14.4) for the 'morning' group and the 'afternoon' one, respectively (p < 0.001). Multivariable analyses identified 'morning' timing as a significant predictor of longer PFS and OS, with respective HR values of 0.26 (0.11-0.58) and 0.17 (0.08-0.37). The timing effect was consistent across all patient subgroups tested. CONCLUSIONS: Nivolumab was nearly four times as effective following 'morning' as compared to 'afternoon' 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.

Evaluation and Management of Sleep and Circadian Rhythm Disturbance in Cancer.

OPINION STATEMENT: Sleep and circadian rhythm disturbance are among the most commonly experienced symptoms in patients with cancer. These disturbances occur throughout the spectrum of cancer care from diagnosis, treatment, and long into survivorship. The pathogenesis of these symptoms and disturbances is based on common inflammatory pathways related to cancer and its' treatments. The evaluation of sleep and circadian disorders requires an understanding of how these symptoms cluster with other cancer-related symptoms and potentiate each other. A thorough evaluation of these symptoms and disorders utilizing validated diagnostic tools, directed review of clinical information, and diagnostic testing is recommended. Treatment of sleep and circadian disturbance in cancer patients should be based on the findings of a detailed evaluation, including specific treatment of primary sleep and circadian disorders, and utilize integrative and personalised management of cancer-related symptoms through multiple pharmacologic and non-pharmacologic modalities. Recognition, evaluation, and treatment of sleep and circadian rhythm disturbance in cancer may lead to improved symptom management, quality of life, and outcomes.

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 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.

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

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.

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.

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.

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

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.