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Introduction: Treating the early phase of schizophrenia is crucial for preventing further episodes and improving quality of life, functioning, and social inclusion. Pharmacotherapies are first-line treatments, but have limitations. There is consensus on the need for non-pharmacological interventions for individuals in the early phase of schizophrenia. Several psychological interventions have shown promising effects; however, their comparative effectiveness remains largely unknown. To address this issue, a network meta-analysis will be performed. We aim to develop a hierarchy of existing psychological treatments concerning their efficacy and tolerability, which will inform treatment guidelines. Protocol: Randomized controlled trials (RCTs) investigating psychological interventions for first-episode psychosis, first-episode schizophrenia, or early phase schizophrenia will be included. The primary outcome will be overall schizophrenia symptoms (measured up to 6 and 12 months, and at the longest follow-up) and relapse as a co-primary outcome. Secondary outcomes are premature discontinuation; change in positive, negative, and depressive symptoms of schizophrenia; response; quality of life; overall functioning; satisfaction with care; adherence; adverse events; and mortality. The study selection and data extraction are performed by two independent reviewers. We will assess the risk of bias of each study using the Cochrane Risk of Bias tool 2 and evaluate the confidence in the results using Confidence in Network Meta-Analysis (CINeMA). Subgroup and sensitivity analyses will be conducted to explore heterogeneity and assess the robustness of our findings. Discussion: This systematic review and network meta-analysis aims to compare multiple existing psychological interventions, establishing which are best for symptom reduction, relapse prevention, and other important outcomes in early phase schizophrenia. Our results may provide practical guidance concerning the most effective psychological intervention to reduce symptom severity and the societal burden associated with the disorder.

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Clinical trials, the empirical discipline of medical experimentation conducted on human subjects, have engendered a paradigm shift in medical research. The need for new clinical studies is paramount in the Middle East and North Africa (MENA) region, with its rising cancer incidence and demand for efficient oncology treatments. This paper comprehensively reviews the challenges, opportunities, and future directions of phase I oncology clinical trials in the MENA region. Early-phase trials are vital in determining drug dosage and assessing toxicity, bridging the gap between preclinical research and clinical practice. Considering the unique landscape of MENA, this review explores regulatory aspects, specific hurdles faced, potential advantages, and areas for improvement in conducting these trials. Various future directions can be pursued to maximize the potential of phase I oncology trials in MENA. While regulatory bodies like the Ministry of Health adhere to the International Conference on Harmonization-Good Clinical Practice guidelines, a unified system meeting high standards would yield better results. Strengthening research infrastructure, establishing research centers, incorporating clinical trial education into the curriculum, and improving access to medical facilities are crucial. Enhancing consumer understanding of research would facilitate increased participation and promote sustainability in trial recruitment. Navigating various funding sources would open the door for more funding opportunities. Collaborations between academia, industry, and regulatory bodies, both international and local, should be fostered to promote knowledge sharing, resource pooling, and harmonization of standards. Such collaborations would contribute to the sustainability of clinical trial activities by leveraging collective expertise, sharing research infrastructure, and distributing the burden of regulatory compliance. By adopting these strategies, the MENA region can advance its capacity to conduct early phases of oncology trials and contribute significantly to the global medical research landscape.

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Aim: To study Swedish pediatric oncologists' practical and emotional experiences of referring, including and/or treating children in early-phase clinical trials. Methods: A nationwide study was conducted using a mixed-method approach. Structured interviews based on a study-specific questionnaire and participants' personal reflections were utilized. Survey responses were analyzed using descriptive statistics, while participants' comments were analyzed using thematic analysis. All interviews were recorded and transcribed verbatim. Results: In total, 29 physicians with 4 to 32 years of experience in pediatric oncology participated, with 19 (66%) having > 10 years of experience. Three themes appeared: 1) Optimization-based approach focused on finding the most suitable treatment and care for every child with a refractory/relapsed cancer eligible for an early-phase clinical trial; 2) Team-based approach aimed at establishing local and national consensus in decision-making for treatment options, including early-phase clinical trials and palliative care; 3) Family-based approach in which the physicians provided families with actionable information, listened to their desires, and endeavored to maintain hope in challenging circumstances. Several participants (40% with ≤ 10 years of experience and 58% with > 10 years of experience) viewed the early-phase clinical trial as a potential "chance of cure". A majority (80%) of physicians with ≤ 10 years of experience, reported that they often or always felt personally and emotionally affected by communication regarding early-phase clinical trials. Delivering difficult news in cases of uncertain prognosis was identified as the major challenge. None of the study participants felt adequately prepared in terms of sufficient knowledge and experience regarding early-phase clinical trials. The physicians expressed a need for guidance and training in communication to address these challenges. Conclusions: Working with early-phase clinical trials highlight a field where physicians cannot solely rely on their expertise or past experiences, and where they are likely to be deeply emotionally involved. Physicians who care for children eligible for such studies require targeted educational initiatives and supervision.

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BACKGROUND: Interstitial lung disease (ILD) encompasses a heterogeneous group of disorders sharing pathophysiological inflammatory mechanisms, leading to parenchymal distortions. The prevalence of ILD with new cancer drugs is underreported: the identification of potential determinants is priority. MATERIALS AND METHODS: ILDE is a retrospective study aimed at describing the clinical course and potential determinants of ILD in patients receiving experimental treatments. RESULTS: We identified 226 eligible patients, of whom 5.3% (n = 12) had ILD. In five patients, the diagnosis was radiological, while seven patients had initial cough, dyspnea, fatigue or fever. ILD was graded as grade 1 (G1) in four, G2 in five and G3 in three patients. The first occurrence of ILD resolved completely in 50% of patients (n = 6/12). No patient had fatal ILD. Eight patients (66.7%) resumed the treatment after the first episode of ILD, while four patients (33.3%) had to discontinue the therapy. Five out of six patients had resolved the first ILD episode and then resumed treatment, experiencing a second ILD episode (n = 5/6; 83.3%). The second ILD event was G1 in three patients and G2 in two patients, resulting in three patients who eventually discontinued the treatment (n = 3/5; 60%). Correlation analysis showed a higher risk of ILD in older patients (P = 0.051), those who had received previous chest radiation therapy (P = 0.047) or those receiving antibody-drug conjugates (P = 0.006). In a survival analysis adjusted for immortal time bias, ILD was not independently prognostic (hazard ratio 0.50, 95% confidence interval 0.23-1.09, P = 0.082). CONCLUSIONS: In ILDE, patients experiencing ILD had generally good outcomes, and many could resume the cancer treatments. Implementing best practices to prompt diagnosis and management of ILD is critical to treat a potentially severe adverse effect of new drugs, while not affecting patients' outcomes. Research efforts to identify risk factors is warranted, to implement risk-based monitoring schedules and develop ad hoc strategies to improve the cure rates of ILD.

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Over the past decade, there has been extensive research on the mismatch negativity (MMN) and its promise as a biomarker of illness in people with schizophrenia (SZ). Nevertheless, when attempting to assess the early stages of illness progression, the utility of MMN has been inconsistent. Recently, researchers have been investigating a more advanced MMN paradigm (the complex MMN [cMMN]) which is believed to index higher-order cognitive processing and has been suggested to be a more effective indicator of the early phases of SZ. The cMMN is defined as a paradigm that relies on alterations within a pre-established pattern of stimuli. In this meta-analysis, we investigated cMMN deficits in individuals with SZ, including an analysis involving those in the first 5 years of illness. Our search also included individuals with bipolar disorder who experience psychosis; however, no related papers were found and thus, no findings are reported. Our findings indicate a small/moderate effect (d = 0.47), suggesting that individuals with SZ exhibit reduced cMMN amplitudes compared to individuals without SZ. Interestingly, this effect seems to be more pronounced in individuals within the first 5 years of their illness (d = 0.58), suggesting that cMMN might be a more sensitive biomarker in the early phases of SZ compared to traditional paradigms.

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Using electroencephalography (EEG) to examine the simple mismatch negativity (MMN), a marker of auditory cortex function, has been of great interest in the exploration of biomarkers for psychotic illness. Despite many studies reporting MMN deficits in chronic schizophrenia, there are inconsistent reports of MMN reductions in the early phases of psychotic illness, suggesting the MMN elicited by traditional paradigms may not be a sensitive enough measure of vulnerability to be used as a biomarker. Recently, a more computationally complex measure of auditory cortex function (the complex mismatch negativity; cMMN) has been hypothesized to provide a more sensitive marker of illness vulnerability. The current study employed a novel dual rule paradigm, in which two pattern rules are established and violated, to examine the cMMN in 14 individuals with early phase psychosis (EPP, < 5 years illness) and 15 healthy controls (HC). Relationships between cMMN waveforms, symptom severity, and measures of functioning were explored. We found reductions of cMMN amplitudes at the site of maximal amplitude in EPP (p = .017) with large effect sizes (Hedges' g = 0.96). This study is an early step in the exploration of the cMMN as a biomarker for psychosis. Our results provide evidence that the dual rule cMMN paradigm shows promise as a method for cMMN elicitation that captures more subtle neurofunctional changes in the early stages of illness.

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Understanding the genesis and early-phase reactions of iron corrosion is essential for the early detection, mitigation and prevention of metal degradation. In this work, high-resolution 3D tomography of metallic iron oxidation was acquired using high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM). In particular, dendritic capillaries (<0.5 nm) were observed during the initial oxidation of fresh nanoscale zero-valent iron due to the differential oxygen diffusion and iron atoms migration. This observation led to the proposal of a nanoscale "pothole" model for early-phase corrosion, wherein hollowing out of the metal nanoparticle and formation of nanovoids beneath the iron/oxide interface through Kirkendall effect. Coalescence of the nanocapillaries results in the ultimate collapse of metal structure and/or functional failure. Using nanoscale zero-valent iron as a research model, this work provides unprecedented insights into the nano- and atomic-scale mechanisms of iron oxidation, paving the way for advanced detection and prevention strategies for iron corrosion.

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BACKGROUND: Elderly patients are underrepresented in clinical trials, particularly in early-phase studies. Our study assessed the safety and efficacy of novel anti-cancer treatments investigated in early-phase clinical trials, comparing outcomes between younger and elderly patients. METHODS: This retrospective study analyzed data from patients enrolled in phase I/II trials at our center between January 2014 and April 2021. We evaluated clinicopathologic characteristics, toxicity, and clinical efficacy, categorizing patients into younger (≤ 65 years) and elderly (> 65 years) groups. RESULTS: 419 patients were included with a median age of 56 years. Among these, 107 (26 %) were older than 65 years. Predominant cancers included breast (48 %), lung (10 %), and melanoma (5 %). Patients were treated in 64 trials, predominantly receiving immunotherapy-based (47 %) or targeted therapy-based (45 %) treatment. Elderly presented with poorer ECOG performance status (P = 0.001) and had fewer prior therapy lines (P = 0.01) than younger patients. Grade ≥ 3 adverse events (AEs) were similar across age groups (31 % younger vs 33 % elderly; P = 0.7), including in combination therapy scenarios. However, elderly patients experienced more AEs with antibody-drug conjugates compared to younger counterparts (56 % vs 14 %, P = 0.036) and were more likely to discontinue treatment due to toxicity (15 % vs 7 %; P = 0.011). No significant age-related differences in response rates and survival outcomes were observed across treatment modalities, except for immunotherapy-based regimens for which elderly patients exhibited higher response rates, disease control rates, and prolonged progression-free survival. CONCLUSIONS: Our findings suggest that elderly exhibit comparable safety and efficacy outcomes to younger patients in early-phase clinical trials for new cancer drugs. This underscores the importance of including elderly patients in phase I/II trials to ensure the generalizability of study results and mitigate age-related disparities in cancer treatment access.

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BACKGROUND: Experience-Based Co-Design (EBCD) is a multi-stage participatory action research process which was developed originally to increase patient involvement in service improvement initiatives. This viewpoint article serves as a reflection on the researchers' experiences, focusing on the application and feasibility of participatory approaches, particularly co-design, in the specific context of early-phase clinical trials. METHODS: We reflect on the opportunities and challenges of applying EBCD in a new context of early-phase clinical trials in oncology where experimental treatments are increasingly perceived as a therapeutic option and, in certain instances, their efficacy may lead to accelerated approval facilitating a swifter integration into standard care. RESULTS: We propose that the opportunity of applying EBCD in such trials lies in improving the delivery of person-centered care, care coordination, and support during the transition from experimental to standard care. Three potential challenges when applying EBCD in early-phase clinical trials are discussed related to: the need for standardization in trial processes; planning EBCD in a context of high uncertainty; and vulnerability of patient populations. CONCLUSION: Integrating EBCD into early-phase oncology trials presents an opportunity to enhance person-centered care and can lead to simultaneous improvements in care processes and therapeutic development. PATIENT OR PUBLIC CONTRIBUTION: This article has been developed with the collaboration of a patient partner who serves on the advisory board of our ongoing EBCD study in early clinical trials.

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BACKGROUND: Phase 1 oncology trials provide access to new therapies and may improve cancer outcomes. Phase 1 trials conducted in the Asian-Pacific region are increasing at a faster rate than the global trend. This study aimed to describe the changing landscape of phase 1 oncology trials in Australia in the last decade. METHODS: This cross-sectional study reviewed phase 1 oncology trials registered on ClinicalTrials.gov conducted in Australia. Phase 1 trials were included for analysis if they enrolled adults with solid organ malignancies, used at least one systemic agent, and were first registered between January 1, 2012, and December 31, 2022. The number of trials, site locations, sponsor type, and drug class were analyzed using descriptive statistics. RESULTS: Over the 10-year period, ClinicalTrials.gov included 493 phase 1 clinical trials across 71 Australian sites. Most sites were in metropolitan locations; in Melbourne, trials were concentrated within selected sites, while in Sydney, trials were spread across a larger number of sites. The number of phase 1 trials per annum increased from 18 in 2012 to 75 in 2022. Since 2020, emerging biopharmaceutical companies have become the predominant sponsor type, a trend that is also seen globally. While most trial sponsors were North American (42%), there was increasing representation from Asian sponsors over the 10-year period (6% in 2012 to 39% in 2022). Immunomodulatory (45%) and targeted approaches (44%) accounted for most drug classes used alone or in combination. CONCLUSIONS: There are an increasing number of phase 1 trials conducted within Australia. Sponsors of phase 1 trials are increasingly from Asian countries and are more likely to be emerging biopharmaceutical companies.

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INTRODUCTION: Recent work suggests that amyloid beta (Aß) positron emission tomography (PET) tracer uptake shortly after injection ("early phase") reflects brain metabolism and perfusion. We assessed this modality in a predominantly amyloid-negative neurodegenerative condition, Parkinson's disease (PD), and hypothesized that early-phase 18F-florbetaben (eFBB) uptake would reproduce characteristic hypometabolism and hypoperfusion patterns associated with cognitive decline in PD. METHODS: One hundred fifteen PD patients across the spectrum of cognitive impairment underwent dual-phase Aß PET, structural and arterial spin labeling (ASL) magnetic resonance imaging (MRI), and neuropsychological assessments. Multiple linear regression models compared eFBB uptake to cognitive performance and ASL MRI perfusion. RESULTS: Reduced eFBB uptake was associated with cognitive performance in brain regions previously linked to hypometabolism-associated cognitive decline in PD, independent of amyloid status. Furthermore, eFBB uptake correlated with cerebral perfusion across widespread regions. DISCUSSION: EFBB uptake is a potential surrogate measure for cerebral perfusion/metabolism. A dual-phase PET imaging approach may serve as a clinical tool for assessing cognitive impairment. Highlights: Images taken at amyloid beta (Aß) positron emission tomography tracer injection may reflect brain perfusion and metabolism.Parkinson's disease (PD) is a predominantly amyloid-negative condition.Early-phase florbetaben (eFBB) in PD was associated with cognitive performance.eFBB uptake reflects hypometabolism-related cognitive decline in PD.eFBB correlated with arterial spin labeling magnetic resonance imaging measured cerebral perfusion.eFBB distinguished dementia from normal cognition and mild cognitive impairment.Findings were independent of late-phase Aß burden.Thus, eFBB may serve as a surrogate measure for brain metabolism/perfusion.

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Background: Long-acting injectable antipsychotics (LAIs) have advantages over oral antipsychotics (OAPs) in preventing relapse and hospitalization in chronically ill patients with schizophrenia-spectrum disorders (SSDs), but evidence in patients with first-episode/recent-onset, that is, early-phase-SSDs is less clear. Objectives: To assess the relative medium- and long-term efficacy and safety of LAIs versus OAPs in the maintenance treatment of patients with early-phase SSDs. Method: We searched major electronic databases for head-to-head randomized controlled trials (RCTs) comparing LAIs and OAPs for the maintenance treatment of patients with early-phase-SSDs. Design: Pairwise, random-effects meta-analysis. Relapse/hospitalization and acceptability (all-cause discontinuation) measured at study-endpoint were co-primary outcomes, calculating risk ratios (RRs) with their 95% confidence intervals (CIs). Subgroup analyses sought to identify factors moderating differences in efficacy or acceptability between LAIs and OAPs. Results: Across 11 head-to-head RCTs (n = 2374, median age = 25.2 years, males = 68.4%, median illness duration = 45.8 weeks) lasting 13-104 (median = 78) weeks, no significant differences emerged between LAIs and OAPs for relapse/hospitalization prevention (RR = 0.79, 95%CI = 0.58-1.06, p = 0.13) and acceptability (RR = 0.92, 95%CI = 0.80-1.05, p = 0.20). The included trials were highly heterogeneous regarding methodology and patient populations. LAIs outperformed OAPs in preventing relapse/hospitalization in studies with stable patients (RR = 0.65, 95%CI = 0.45-0.92), pragmatic design (RR = 0.67, 95%CI = 0.54-0.82), and strict intent-to-treat approach (RR = 0.64, 95%CI = 0.52-0.80). Furthermore, LAIs were associated with better acceptability in studies with schizophrenia patients only (RR = 0.87, 95%CI = 0.79-0.95), longer illness duration (RR = 0.88, 95%CI = 0.80-0.97), unstable patients (RR = 0.89, 95%CI = 0.81-0.99) and allowed OAP supplementation of LAIs (RR = 0.90, 95%CI = 0.81-0.99). Conclusion: LAIs and OAPs did not differ significantly regarding relapse prevention/hospitalization and acceptability. However, in nine subgroup analyses, LAIs were superior to OAPs in patients with EP-SSDs with indicators of higher quality and/or pragmatic design regarding relapse/hospitalization prevention (four subgroup analyses) and/or reduced all-cause discontinuation (five subgroup analyses), without any instance of OAP superiority versus LAIs. More high-quality pragmatic trials comparing LAIs with OAPs in EP-SSDs are needed. Trial registration: CRD42023407120 (PROSPERO).

OBJECTIVE: We aimed to uncover whether LAIs or regular antipsychotic pills demonstrate better outcomes over the medium and long term for individuals in the early stages of schizophrenia. METHOD: We scrutinized several studies comparing LAIs to regular pills in treating early-stage schizophrenia. Employing a combined analysis, we assessed factors such as preventing relapses and hospitalizations, as well as patient treatment adherence. DESIGN: We combined different study results in one unique analysis. We delved into whether LAIs surpassed regular pills in preventing relapses and hospitalizations and in patient treatment adherence. RESULTS: In our study of 11 trials involving over 2000 participants, we observed that LAIs and regular antipsychotic pills were generally comparable regarding preventing relapses, hospitalizations, and treatment adherence. However, on closer inspection, LAIs appeared slightly more effective for specific groups in the early stages of schizophrenia. CONCLUSION: While LAIs and regular antipsychotic pills showed similar results for most individuals in the early stages of schizophrenia, our findings hint at the possibility that LAIs might have a slight edge for certain groups. Nevertheless, we emphasize the need for more high-quality studies to gain a clearer understanding. REGISTRATION: This study is registered under CRD42023407120 (PROSPERO).

Comparing long-acting injections and pills for early schizophrenia: a study review and combined analysis Background: We explored whether antipsychotics long-acting injections (LAIs) might outperform regular antipsychotics pills for people dealing with early-stage conditions like schizophrenia. While LAIs have clear benefits for those with long-term challenges, their effectiveness for those just starting to grapple with these issues is less certain.

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PURPOSE: The integration of palliative care (PC) into oncological management is recommended well before the end of life. It improves quality of life and symptom control and reduces the aggressiveness of end-of-life care. However, its appropriate timing is still debated. Entry into an early-phase clinical trial (ECT) represents hopes for the patient when standard treatments have failed. It is an opportune moment to integrate PC to preserve the patient's general health status. The objective of this study was to evaluate the motives for acceptance or refusal of early PC management in patients included in an ECT. METHODS: Patients eligible to enter an ECT were identified and concomitant PC was proposed. All patients received exploratory interviews conducted by a researcher. Their contents were analyzed in a double-blind thematic analysis with a self-determination model. RESULTS: Motives for acceptance (PC acceptors: n = 27) were both intrinsic (e.g., pain relief, psychological support, anticipation of the future) and extrinsic (e.g., trust in the medical profession, for a relative, to support the advance of research). Motives for refusal (PC refusers: n = 3) were solely intrinsic (e.g., PC associated with death, negative representation of psychological support, no need for additional care, claim of independence). CONCLUSIONS: The motives of acceptors and refusers are not internalized in the same way and call for different autonomy needs. Acceptors and refusers are influenced by opposite representations of PC and a different perception of mixed management.

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Traditional approaches in dose-finding trials, such as the continual reassessment method, focus on identifying the maximum tolerated dose. In contemporary early-phase dose-finding trials, especially in oncology with targeted agents or immunotherapy, a more relevant aim is to identify the lowest dose level that maximises efficacy whilst remaining tolerable. Backfilling, defined as the practice of assigning patients to dose levels lower than the current highest tolerated dose, has been proposed to gather additional pharmacokinetic, pharmacodynamic and biomarker data to recommend the most appropriate dose to carry forward for subsequent studies. The first formal framework [5] for backfilling proposed randomising backfill patients with equal probability among those doses below the dose level where the study is currently at. Here, we propose to use Bayesian response-adaptive randomisation to backfill patients. This patient-oriented approach to backfilling aims to allocate more patients to dose levels in the backfill set with higher expected efficacy based on emerging data. The backfill set constitutes of the doses below the dose the dose-finding algorithm is at. At study completion, collective patient data inform the dose-response curve, suggesting an optimal dose level balancing toxicity and efficacy. Our simulation study across diverse clinical trial settings demonstrates that a backfilling strategy using Bayesian response-adaptive randomisation can result in a patient-oriented patient assignment procedure which simultaneously enhances the likelihood of correctly identifying the most appropriate dose level. This contribution offers a methodological framework and practical implementation for patient-oriented backfilling, encompassing design and analysis considerations in early-phase trials.

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PURPOSE: This study aimed to evaluate the factors associated with retinal pigment epithelium (RPE) tear development in the early phase after anti-vascular endothelial growth factor (VEGF) drug initiation in eyes with neovascular age-related macular degeneration (nAMD) and retinal pigment epithelial detachment (PED). METHODS: Treatment-naive eyes with nAMD and PED for which anti-VEGF drug injections had been initiated and followed up for at least 3 months after the 1st anti-VEGF drug injection, were retrospectively investigated. Baseline characteristics of the PEDs, including type, height, and area, were evaluated using fundus photographs, fluorescein angiography, and optical coherence tomography images. The association between patient age, sex, medical history, PED characteristics, and the development of RPE tears within 3 months of starting anti-VEGF therapy was examined. RESULTS: This study included 244 eyes (230 patients; mean age 75.0 years, 159 males and 71 females). RPE tears occurred in 13 eyes (5.3%) within 3 months of the start of anti-VEGF therapy. Multivariate analysis showed an association of the development of RPE tears with PED height (every 100 µm, odds ratio [OR]: 1.50, 95% confidence interval [CI]: 1.07-2.12, p = 0.019), PED area (every 10 mm2, OR: 3.02, CI: 1.22-7.46, p = 0.016), and the presence of fibrovascular PED (OR: 59.22, CI: 4.12-850.59, p = 0.002). Eyes with cleft (the hypo-reflective space beneath the fibrovascular PED) were more likely to develop an RPE tear (p = 0.01, χ-square test). CONCLUSIONS: Fibrovascular PED, large PED area, high PED height, and the cleft finding are independent risk factors for the development of RPE tears early after the administration of anti-VEGF drugs.

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Advancements in cancer treatment have led to improved survival rates, with early phase clinical trials (EPCTs) serving as important initial steps in evaluating novel therapies. Recent studies have shown that response rates in these trials have doubled in the last twenty years. Patients who enroll on EPCTs have advanced cancer and heightened symptomatology yet maintain a robust performance status that qualifies them for clinical trial participation. It is well established that many of these patients have needs that can be addressed by palliative care, including symptom management, value assessments, advance care planning, and psychosocial and spiritual support. Several small studies have aimed to identify the most beneficial palliative care intervention for this cohort of patients, ranging from formal clinic-based multidisciplinary palliative care interventions to home-based interventions. While outcomes have trended towards benefit for patients, especially pertaining to psychological well-being, most studies were not powered to detect additional benefits for improved physical symptom management, reduction in care utilization or increased length of time on trial. In this review, we discuss the unique palliative care needs of this population and what we can learn from results of past interventional studies. We advocate for a tailored palliative care approach that acknowledges the time toxicity experienced by patients enrolled in EPCTs and address challenges posed by shortages within the palliative care workforce.

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INTRODUCTION: As tumour response rates are increasingly demonstrated in early-phase cancer trials (EPCT), optimal patient selection and accurate prognostication are paramount. Hammersmith Score (HS), a simple prognostic index derived on routine biochemical measures (albumin <35 g/L, lactate dehydrogenase >450 IU/L, sodium <135 mmol/L), is a validated predictor of response and survival in EPCT participants. HS has not been validated in the cancer immunotherapy era. METHODS: We retrospectively analysed characteristics and outcomes of unselected referrals to our early-phase unit (12/2019-12/2022). Independent predictors for overall survival (OS) were identified from univariable and multivariable models. HS was calculated for 66 eligible trial participants and compared with the Royal Marsden Score (RMS) to predict OS. Multivariable logistic regression and C-index was used to compare predictive ability of prognostic models. RESULTS: Of 212 referrals, 147 patients were screened and 82 patients treated in EPCT. Prognostic stratification by HS identifies significant difference in median OS, and HS was confirmed as a multivariable predictor for OS (HR: HS 1 vs. 0 2.51, 95% CI: 1.01-6.24, p = 0.049; HS 2/3 vs. 0: 10.32, 95% CI: 2.15-49.62, p = 0.004; C-index 0.771) with superior multivariable predictive ability than RMS (HR: RMS 2 vs. 0/1 5.46, 95% CI: 1.12-26.57, p = 0.036; RMS 3 vs. 0/1 6.83, 95% CI: 1.15-40.53, p < 0.001; C-index 0.743). CONCLUSIONS: HS is a validated prognostic index for patients with advanced cancer treated in the context of modern EPCTs, independent of tumour burden. HS is a simple, inexpensive prognostic tool to optimise referral for EPCT.

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BACKGROUND/AIM: Early phase clinical trials (EPCTs) assess the tolerability of novel anti-cancer therapeutics in patients with advanced malignancy. Patient selection is important given the modest clinical benefit and time commitments for trials. Prognostic scores have been developed to facilitate identification of high-risk patients. This study aimed to compare five prognostic scores to predict survival for patients on an EPCT. PATIENTS AND METHODS: We performed a retrospective review of patients enrolled in EPCT at Liverpool Hospital, Sydney, from 2013 to 2023. Demographic, biochemical, and survival data were collected from electronic medical records. The score from five prognostic scoring systems (Royal Marsden hospital, MD Anderson Cancer centre, Gustave Roussy Immune, MD Anderson Immune Checkpoint Inhibitor and Princess Margaret Hospital Index) were calculated. Overall survival was measured using the Kaplan-Meier method and predictive discrimination was assessed using Harrell's c-index. RESULTS: A total of 218 patients across 36 EPCTs were included. The median overall survival was 9.8 months with 22% of patients dying in less than 90 days. Seventeen to thirty-four percent of patients were categorised as high-risk. The MDACC score obtained the highest predictability for overall survival for the whole cohort (c-index=0.67, 95%CI=0.62-0.72) and the immunotherapy-based cohort (c-index= 0.65, 95%CI=0.59-0.71). However, all scores performed similarly with a significant overlap in the confidence intervals. CONCLUSION: Our retrospective audit confirms the utility of prognostic scores to predict survival in an Australian EPCT cohort, with similar predictive discrimination across various scoring systems. Integration of these prognostic tools into EPCT screening processes may optimise benefits and reduce risks associated with EPCTs.

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BACKGROUND: Participants considering early-phase cancer clinical trials (CTs) need to understand the unique risks and benefits prior to providing informed consent. This qualitative study explored the factors that influence patients' decisions about participating in early-phase cancer immunotherapy CTs through the ethical lens of relational autonomy. METHODS: Using an interpretive descriptive design, interviews were conducted with 21 adult patients with advanced cancer who had enrolled in an early-phase CT. Data was analyzed using relational autonomy ethical theory and constant comparative analysis. RESULTS: The extent to which participants perceived themselves as having a choice to participate in early-phase cancer immunotherapy CTs was a central construct. Perceptions of choice varied according to whether participants characterized their experience as an act of desperation or as an opportunity to receive a novel treatment. Intersecting psychosocial and structural factors influenced participants' decision making about participating in early-phase cancer immunotherapy trials. These relational factors included: (1) being provided with hope; (2) having trust; (3) having the ability to withdraw; and (4) timing constraints. CONCLUSIONS: Findings highlight the continuum of perceived choice that exists among patients with cancer when considering participation in early-phase cancer immunotherapy CTs. All participants were interpreted as exhibiting some degree of relational autonomy within the psychosocial and structural context of early-phase CT decision making. This study offers insights into the intersection of cancer care delivery, personal beliefs and values, and established CT processes and structures that can inform future practices and policies associated with early-phase cancer immunotherapy CTs to better support patients in making informed decisions.

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