Tolerability Of Treatment Research Articles

Mesna, Doxorubicin, Ifosfamide and Dacarbazine (MAID) Combination Chemotherapy for Retroperitoneal Sarcoma: A Single-center Experience.

There is limited evidence regarding the systemic treatment of retroperitoneal soft-tissue sarcoma, and the current Japanese guidelines fail to make definitive suggestions. Here, we report our experience with combination chemotherapy of mesna, doxorubicin, ifosfamide, and dacarbazine (MAID) in this population. We retrospectively reviewed the records of eight patients (three male and five female) who received MAID for pathologically diagnosed metastatic unresectable retroperitoneal sarcoma (either leiomyosarcoma or pleomorphic sarcoma) between October 2019 and January 2022. Treatment efficacy, tolerability (need for dose reduction), and safety profiles were evaluated and summarized. At initiation, the median age was 56.0 years, and the body mass index was 20.0 kg/cm2 Six patients had Eastern Cooperative Oncology Group performance status scores of 0. The net clinical benefit was a partial response in three (37.5%) patients, stable disease in four (50.0%), and progressive disease in one (12.5%). During the median 90.8 weeks of follow-up, disease in five patients progressed, resulting in a median progression-free survival of 48.4 weeks, and five deaths occurred, resulting in an overall survival of 95.1 weeks. Commonly observed adverse events were neutropenia (eight patients), anemia (eight patients), and decreased platelet count (seven patients), which led to dose reduction (60-80%) in six patients. MAID combination therapy may be an acceptable option for advanced retroperitoneal sarcoma; however, its benefits must be carefully assessed owing to its not insignificant toxicity.

Non-viral-mediated gene transfer of OX40 ligand for tumor immunotherapy.

Immune checkpoint blockade (ICB) is rapidly becoming a standard of care in the treatment of many cancer types. However, the subset of patients who respond to this type of therapy is limited. Another way to promote antitumoral immunity is the use of immunostimulatory molecules, such as cytokines or T cell co-stimulators. The systemic administration of immunotherapeutics leads to significant immune-related adverse events (irAEs), therefore, the localized antitumoral action is needed. One way to achieve this is intratumoral non-viral gene-immune therapy, which allows for prolonged and localized gene expression, and multiple drug administration. In this study, we combined the previously described non-viral gene delivery system, PEG-PEI-TAT copolymer, PPT, with murine OX40L-encoding plasmid DNA. The resulting OX40L/PPT nanoparticles were characterized via gel mobility assay, dynamic light scattering analysis and in vitro transfection efficiency evaluation. The antitumoral efficacy of intratumorally (i.t.) administered nanoparticles was estimated using subcutaneously (s.c.) implanted CT26 (colon cancer), B16F0 (melanoma) and 4T1 (breast cancer) tumor models. The dynamics of stromal immune cell populations was analyzed using flow cytometry. Weight loss and cachexia were used as irAE indicators. The effect of combination of i.t. OX40L/PPT with intraperitoneal PD-1 ICB was estimated in s.c. CT26 tumor model. The obtained OX40L/PPT nanoparticles had properties applicable for cell transfection and provided OX40L protein expression in vitro in all three investigated cancer models. We observed that OX40L/PPT treatment successfully inhibited tumor growth in B16F0 and CT26 tumor models and showed a tendency to inhibit 4T1 tumor growth. In B16F0 tumor model, OX40L/PPT treatment led to the increase in antitumoral effector NK and T killer cells and to the decrease in pro-tumoral myeloid cells populations within tumor stroma. No irAE signs were observed in all 3 tumor models, which indicates good treatment tolerability in mice. Combining OX40L/PPT with PD-1 ICB significantly improved treatment efficacy in the CT26 subcutaneous colon cancer model, providing protective immunity against CT26 colon cancer cells. Overall, the anti-tumor efficacy observed with OX40L non-viral gene therapy, whether administered alone or in combination with ICB, highlights its potential to revolutionize cancer gene therapy, thus paving the way for unprecedented advancements in the cancer therapy field.

OPTImal PHARMacological therapy for patients with heart failure: Rationale and design of the OPTIPHARM-HF registry.

Patients with heart failure (HF) remain often undertreated for multiple reasons, including treatment inertia, contraindications, and intolerance. The OPTIimal PHARMacological therapy for patients with Heart Failure (OPTIPHARM-HF) registry is designed to evaluate the prevalence of evidence-based medical treatment prescription and titration, as well as the causes of its underuse, in a broad real-world population of consecutive patients with HF across the whole ejection fraction spectrum and among different clinical phenotypes. The OPTIPHARM-HF registry (NCT06192524) is a prospective, multicenter, observational, national study of adult patients with symptomatic HF, as defined by current international guidelines, regardless of ejection fraction. Both outpatients and inpatients with chronic and acute decompensated HF will be recruited. The study will enroll up to 2500 patients with chronic HF at approximately 35 Italian HF centres. Patients will be followed for a maximum duration of 24 months. The primary objective of the OPTIPHARM-HF registry is to assess prescription and adherence to evidence-based guideline-directed medical therapy (GDMT) in patients with HF. The primary outcome is to describe the prevalence of GDMT use according to target guideline recommendation. Secondary objectives include implementation of comorbidity treatment, evaluation of sequence of treatment introduction and up-titration, description of GDMT implementation in the specific HF population, main causes of GDMT underuse, and assessment of cumulative rate of cardiovascular events. The OPTIPHARM-HF registry will provide important implications for improving patient care and adoption of recommended medical therapy into clinical practice among HF patients.

Patient and public involvement and engagement in the development of innovative patient-centric early phase dose-finding trial designs

BackgroundIn light of the FDA’s Project Optimus initiative, there is fresh interest in leveraging Patient-reported Outcome (PRO) data to enhance the assessment of tolerability for investigational therapies within early phase dose-finding oncology trials. Typically, dose escalation in most trial designs is solely reliant on clinician assessed adverse events. Research has shown a disparity between patients and clinicians when assessing whether an investigational therapy is tolerable, leading to the recommendation of potentially intolerable doses for further investigation in subsequent trials.It is also increasingly recognized that patient and public involvement and engagement (PPIE) plays a pivotal role in enriching trial design and conduct. However, to our knowledge, no PPIE has explored the optimal integration of PROs in the development of advanced statistical trial designs within early phase dose-finding oncology trials.MethodsA virtual PPIE session was held with nine participants on 18th October 2023 to discuss the incorporation of PROs within a dose-finding trial design. This cross disciplinary session was developed and led by a team of statisticians, clinical specialists, qualitative experts, and trial methodologists. Following the session, in-depth perspectives were provided by two patient advocates who actively engaged in the PPIE session. We discuss the importance of PPIE in shaping advanced dose-finding trial designs, share insights from patients on integrating PROs to inform treatment tolerability, and present a template for meaningful patient involvement in trial design development.ResultsParticipants generally supported the introduction of PROs within dose-finding trials but showed some apprehensiveness as to how PROs may reduce the size of the recommended dose (and potentially efficacious effect). Some participants shared that they may be reluctant to record the real severity of their symptoms via PROs if it would mean that they would have to discontinue treatment. They discussed that PROs could be used to assess tolerability rather than toxicity of a dose.ConclusionsAmplifying patient voice in the development of patient-centric dose-finding trial designs is now essential. This paper offers an exemplary illustration of how trialists and methodologists can effectively incorporate patient voice in the future development of advanced dose-finding trial designs.

Baseline anemia and its associated factors among adult cancer patients at Northwest Amhara Regional State Referral Hospitals, Northwest Ethiopia, 2021.

Currently, the problem of cancer has been increasing around the world, predominantly in middle- and low-income countries. Anemia, a major and often overwhelming health burden for cancer patients, significantly distorts their quality of life. It is well-established that the length of treatment increases the frequency of anemia, with hematological malignancies experiencing nearly double the rate compared to solid tumors. Despite this established knowledge, data on the prevalence of anemia among cancer patients in Ethiopia remains scarce, according to the investigators. This study aimed to assess the prevalence of baseline anemia and associated factors among adult cancer patients at Northwest Amhara Comprehensive Specialized Hospitals, oncology treatment units, Northwest Ethiopia, in 2021. This study employed an institutional-based cross-sectional design and was conducted in Northwest Amhara Comprehensive Specialized Hospitals. A systematic random sampling technique was used to select 315 participants. The data were collected using interviewer-administered questionnaires and chart reviews of existing medical records using a structured and pretested questionnaire format. The data were entered into Epi. Data version 4.6 and analyzed using Stata version 14.0. Bivariable and multivariable logistic regression were carried out to identify factors associated with anemia. Adjusted odds ratios with a 95% confidence interval and variables with a p-value of < 0.05 were considered significantly associated with anemia. The prevalence of baseline anemia among adult patients with cancer was found to be 34.84%. Being a woman (AOR = 1.97; 95% CI: 1.00-3.87), being underweight (AOR = 1.96; 95% CI: 1.09-3.52), and having stage III cancer (AOR = 2.35; 95% CI: 1.12-3.01) were significantly associated with anemia. The prevalence of baseline anemia among adult cancer patients was significant. Women, cancer patients with an underweight body mass index, and those diagnosed with clinical-stage III cancer were more likely to have baseline anemia. For health policymakers and healthcare providers, it is better to give special attention to female patients, patients who are underweight, and patients with advanced-stage cancer to reduce the risk of developing the outcome. This would allow for timely intervention to manage anemia and potentially improve treatment tolerance and quality of life for cancer patients.

Real-world Effectiveness and Tolerability of Interferon-free Direct-acting Antiviral for 15,849 Patients with Chronic Hepatitis C: A Multinational Cohort Study.

As practice patterns and hepatitis C virus (HCV) genotypes (GT) vary geographically, a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal. This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs, focusing on GT3 and GT6. We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021. The mean age was 62±13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but ≥97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12. In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%).

Tumor Cell Membrane-Encapsulated MLA Solid Lipid Nanoparticles for Targeted Diagnosis and Radiosensitization Therapy of Cutaneous Squamous Cell Carcinoma.

Squamous cell carcinoma (SCC) is a common nonmelanoma skin cancer. Radiotherapy plays an integral role in treating SCC due to its characteristics, such as diminished intercellular adhesion, heightened cell migration and invasion capabilities, and immune evasion. These problems lead to inaccurate tumor boundary positioning and radiotherapy tolerance in SCC treatment. Thus, accurate localization and enhanced radiotherapy sensitivity are imperative for effective SCC treatment. To address the existing limitations in SCC therapy, we developed monoglyceride solid lipid nanoparticles (MG SLNs) and enveloped them with the A431 cell membrane (A431 CM) to create A431@MG. The characterization results showed that A431@MG was spherical. Furthermore, A431@MG had specific targeting for A431 cells. In A431 tumor-bearing mice, A431@MG demonstrated prolonged accumulation within tumors, ensuring precise boundary localization of SCC. We further advanced the approach by preparing MG SLNs encapsulating 5-aminolevulinic acid methyl ester (MLA) and desferrioxamine (DFO) with an A431 CM coating to yield A431@MG-MLA/DFO. Several studies have revealed that DFO effectively reduced iron content, impeding protoporphyrin IX (PpIX) biotransformation and promoting PpIX accumulation. Simultaneously, MLA was metabolized into PpIX upon cellular entry. During radiotherapy, the heightened PpIX levels enhanced reactive oxygen species (ROS) generation, inducing DNA and mitochondrial damage and leading to cell apoptosis. In A431 tumor-bearing mice, the A431@MG-MLA/DFO group exhibited notable radiotherapy sensitization, displaying superior tumor growth inhibition. Combining A431@MG-MLA/DFO with radiotherapy significantly improved anticancer efficacy, highlighting its potential to serve as an integrated diagnostic and therapeutic strategy for SCC.

Smoking patterns and the intention to quit in German cancer patients: a cross-sectional study

BackgroundContinued smoking after a cancer diagnosis can be associated with lower treatment tolerance, poorer outcomes, and reduced quality of life compared to non-smoking cancer patients or to those who have quit. Yet about 60% of patients continue to smoke after being diagnosed and find it difficult to quit. To address this problem, it is necessary to identify current and past smoking patterns (e.g., frequency of use, types of tobacco products) and determine whether there is motivation to quit. Similarly, factors associated with continued smoking should be identified. These data will provide the basis for the development of smoking cessation programs tailored to the needs of cancer patients.MethodsA questionnaire was distributed to cancer patients older than 18 years in a German Comprehensive Cancer Center. Participating cancer patients were divided into three main groups: 1) patients who stopped smoking before being diagnosed with cancer (Ex-before); 2) patients who stopped smoking after a cancer diagnosis (Ex-after); and 3) patients who currently smoke cigarettes (CS). Sociodemographic, medical, and psychosocial data were collected, as well as smoking patterns and the motivation to quit smoking.ResultsAbout half of patients (51%) who smoked before diagnosis continue to smoke after a cancer diagnosis. Being diagnosed with a tobacco-related cancer type was associated with a decreased probability of continued smoking. Patients with tobacco-related tumors and receiving positive support in burdensome situations were more likely to have a higher cigarette dependence. Of all CS, 59.1% had intention to quit, and 22.7% reported having taken action to quit.The support by a smoking cessation program was considered important. CS were willing to spend up to €100 for support and were open to multiple sessions per week, group sessions, one-on-one sessions and/or online support.ConclusionThese findings underscore the importance of educating cancer patients about the consequences of smoking and to provide them with support to quit. Identified risk factors may further help to recognize cancer patients with high risk of continued smoking after diagnosis.Trial RegistrationThe study was registered at OSF (https://osf.io/3c9km) and published as a study protocol at “https://bmjopen.bmj.com/content/13/4/e069570”.

Quantifying the financial impact of treatment intolerance in chronic myeloid leukemia on oncology clinical practices: A mixed methods study.

e18520 Background: Tyrosine kinase inhibitors (TKIs) have changed the prognosis for patients with chronic myeloid leukemia (CML) to a chronic disease. However, adverse events related to TKI treatment intolerance frequently occur. While the impact of CML treatment intolerance on patient quality of life and cost to health insurers has previously been measured, the time and cost impact to oncology practices is unknown. This mixed methods study aimed to estimate the average time and cost to oncology practices per CML treatment intolerance episode. Methods: The study combined interviews of oncology practice staff with economic modeling. A convenience sample of oncology practice managers was interviewed between October 2023 - January 2024. Interviews aimed to identify and quantify the cost dimensions of addressing treatment intolerance in CML patients. Time impacts reported by respondents were converted into monetary terms using hourly compensation rates of staff needed to complete the identified task. Results: A total of 10 academic oncology practice managers participated in the study. Eight cost dimensions were identified including time spent on prior authorization for medication switch, patient communication, follow-up visits, and care coordination after inpatient stays. Estimated practice time and cost per treatment intolerance episode requiring hospitalization were 34 hours and $3,413 (Table), which were largely attributable to navigating payer prior authorization for medication switch (10 hours, $871), additional follow-up visits (8 hours, $858) and care coordination with inpatient team (9 hours, $782). Activities that could be coded for reimbursement represented only 31.9% of incurred cost. The time and cost per treatment intolerance episode requiring no hospitalization were 17 hours and $1,772. Other burdens not explicitly quantified included negative impact on patient satisfaction, staff morale and care continuity. Conclusions: CML treatment intolerance imposes additional resource and economic burden on oncology practices, and most of these activities are not reimbursed in the current healthcare system. [Table: see text]

Finding the Right Setting for the Right Treatment During the Acute Treatment of Individuals with Schizophrenia: A Narrative Review and Clinical Practice Guideline.

Schizophrenia is most times a chronic and often debilitating illness associated with poor mental health outcomes. Early and effective treatment of schizophrenia in the most appropriate setting can make a significant difference in the long-term recovery. The aim of this narrative review was to provide suggestions and recommendations for effectively managing patients with schizophrenia during acute exacerbations and to enhance awareness and skills related to personalized medicine. A panel of academics and clinicians with experience in the field of psychosis met virtually on July 13th 2023 to narratively review and discuss the research evidence and their clinical experience about the most appropriate acute treatments for patients with schizophrenia. This manuscript represents a synthesis of the panel analysis and discussion. First contact is very important for service users, as is finding the most adequate treatment setting. If patients present to the emergency department, which may be a traumatic setting for service users, a dedicated environment with adequate space and specialized mental health support, including personnel trained in de-escalation techniques, is recommended. A well-connected continuum of care is strongly recommended, possibly with seamless links between inpatient units, day hospital services, outpatient facilities and rehabilitation services. Ideally, this should be structured as part of a coordinated step-down service line. Treatment challenges include suboptimal response, side effects, and nonadherence, which is reduced by the use of long-acting injectable antipsychotics. Individual circumstances, including age, gender, and presence of hostility/aggression or self-harm, cognitive impairment and negative symptoms, comorbidities (depression, substance use disorders) or associated symptoms (anxiety, insomnia), should be considered when selecting the most appropriate treatment for the acute phase of schizophrenia. Efficacy and feasibility, as well as acceptability and tolerability of treatments, require joint consideration from the early stages of schizophrenia, thereby enhancing the possibility of improved short- and long-term outcomes.

Primary treatment modification strategies among older adults with advanced cancer.

1512 Background: Primary treatment modification (PTM; any change in dose or agents of the planned chemotherapy regimen from the standard guidelines) is a common therapeutic approach among older adults with advanced cancer due to their geriatric vulnerabilities. However, strategies to employ these modifications are understudied. This study compares a PTM strategy based on Geriatric Assessment (PTM-GA) intervention vs. usual care strategy based on oncologist’s impression (PTM-UC) on treatment tolerability in older adults with advanced cancer starting new chemotherapy regimens. Methods: In this subgroup analysis of the GAP 70+ study (NCT02054741; PI: Mohile), we included patients aged ≥ 70 with incurable solid tumors who initiated a chemotherapy course with PTM (n=298). For the first (PTM-GA) group, PTM was guided by GA results and recommendations while for the second (PTM-UC) group, PTM was guided by the treating oncologist's estimate only. Tolerability outcomes were assessed within 3 months of treatment and included: 1) any grade 3-5 clinician-rated toxicity according to National Cancer Institute Common Toxicity Criteria; 2) subsequent dose reduction; 3) Activity of Daily Living (ADL) decline; 4) unplanned hospitalization. We used multivariable, cluster-weighted generalized estimating equations models to examine the association of PTM-GA vs. PTM-UC and outcomes adjusting for confounders. Results: Mean age was 77 years. The most common cancer types were gastrointestinal (37%) followed by lung cancer (26%). PTM-GA versus PTM-UC was associated with reduced risk of grade 3-5 toxicity (relative risk (RR)= 0.77, 95% CI, 0.61- 0.90) and subsequent dose reduction (RR, 0.46; 95% CI, 0.29-0.73). Point estimates suggest that patients with PTM-GA may have a lower risk of unplanned hospitalization but results did not reach statistical significance (RR, 0.69; 95% CI, 0.46–1.02). PTM-GA vs. PTM-UC was not associated with ADL decline (RR, 1.05; 95% CI, 0.74–1.49). Conclusions: Older patients with advanced cancer who had PTM guided by GA recommendations had improved treatment tolerability compared to those who PTM based on oncologist’s estimate only. Integrating GA into treatment dosing decisions may lead to improved outcomes in this vulnerable population.

Integrating 4 Methods (In4M) to evaluate physical function in patients with cancer: Results of a comprehensive digital health study.

1564 Background: Physical function (PF) is a core outcome in cancer trials that can inform treatment tolerability. PF can be assessed across modalities including by patient (pt) report, clinician (clin) report, performance tests and digital sensors. The optimal approach for PF measurement has not been defined. Methods: In4M is a prospective observational study evaluating PF in pts initiating chemotherapy for breast cancer or lymphoma followed over 9 months. We used an electronic platform (Hugo) to aggregate serially assessed pt-reported PF, clin- and pt-reported ECOG performance status (PS), 6-minute walk test (6MWT) and wearable (Fitbit) data. We evaluated feasibility in all pts; associations among PF measures and the ability of PF measures to detect change were evaluated in pts with both baseline (BL) and 3-month (3M) data. We used Pearson correlations to assess the relationship of average daily steps with measures of PF. To assess change, we compared each PF measure from BL to 3M using a 2-sided α=.05 paired t-test. Results: Of the208 pts enrolled, 193 (93%) and 159 (76%) completed surveys, and 121 (58%) and 124 (60%) provided wearable data (evaluable: ≥1 day data) at BL and 3M, respectively. When requiring a stringent BL with 4+ days of data with ≥1 weekend day to be evaluable, 88 (42%) and 120 (58%) provided wearable data at BL and 3M. At both BL and 3M, pt-reported PF was generally more highly correlated with wearable-derived daily steps than clin-reported PF and 6MWT were (Table). Significant declines in PF were observed for pt- and clin-reported PF (all p&lt;0.05), but not other modalities. Conclusions: Longitudinalassessment of multi-modal PF data including pragmatic wearable data collection was feasible in pts receiving chemotherapy. Pt-reported PF was the only modality that was both correlated with step count and able to detect change. Additional wearable metrics, correlations among PF measurements and outcomes, and clinically meaningful change scores will be reported. Optimal PF measurement may improve future reporting of treatment tolerability. Clinical trial information: NCT05214144 . [Table: see text]

Real life data of KEYNOTE 522: The Cleveland Clinic experience.

e12612 Background: Triple-negative breast cancer (TNBC) constitutes approximately 15% of all breast cancers and predominantly affects younger women with a disproportionate impact on Black and Hispanic ethnicities. Historically, neoadjuvant therapy centered around chemotherapy alone. However, the KEYNOTE 522 trial has demonstrated improved outcomes with the incorporation of the PD-1 inhibitor Pembrolizumab alongside neoadjuvant chemotherapy. Methods: A retrospective cohort analysis of 106 patients treated with the KEYNOTE 522 regimen within Cleveland Clinic from January 2020 to July 2023. The objective is to evaluate the real-life experience, particularly concerning treatment tolerance and pathologic complete response rates (PCR). Results: Among the 106 female patients, 6.6% completed full neoadjuvant therapy without reporting adverse events (AE), achieving a 71.42% PCR rate. Complications were reported in various subgroups: 54.72% associated with paclitaxel and carboplatin, with discontinuation rates of 60.34%, reduction rates of 33.02%, and full continuation rates of 6.9%. The most prevalent AE included cytopenia (46.55%) and febrile neutropenia, along with other infections (27.59%). For patients discontinuing paclitaxel and carboplatin, the PCR was 68.57%, while with dose reductions, it was 68.75%. Complications related to doxorubicin and cyclophosphamide were reported in 16.04% of patients, with 47.06% either discontinuing or reducing dose, and 5.88% continuing full therapy. Febrile neutropenia, along with other infections (64.71%) and cytopenia (23.53%) were the prominent AE. The PCR for patients discontinuing or reduced doxorubicin and cyclophosphamide was 62.50%. Pembrolizumab-related complications were reported in 16.98% of patients, with a 50% discontinuation rate. The most common AE was dermatologic toxicities (27.78%). The PCR for patients discontinuing pembrolizumab was 83.33% versus 62.5% for those continuing full therapy. Conclusions: This retrospective analysis highlights infections and cytopenias as the primary adverse reactions. Notably, the dose reduction or discontinuation of agents did result in a deterioration of PCR rate compared to patients completing full therapy. Remarkably, PCR was improved for the pembrolizumab discontinuation group, perhaps suggesting a correlation between autoimmune toxicities and improved response. Additional prospective study with larger sample size is needed to understand whether all patients benefit from completing the Keynote 522 regimen. [Table: see text]

REPLACE: A phase III, randomized, open-label trial to evaluate the safety and efficacy of regorafenib and pembrolizumab versus locoregional therapy (LRT) with transarterial chemoembolization (TACE) or transarterial radioembolization (TARE), for the first-line treatment of intermediate-stage hepatocellular carcinoma (HCC) with beyond up-to-7 criteria.

TPS4200 Background: Intermediate-stage HCC represents a heterogeneous population, posing unique challenges for therapeutic management. With the advent of effective systemic therapies for unresectable HCC, the treatment landscape for intermediate-stage extends beyond LRT, particularly in patients with high tumor burden. The growing evidence about the benefit of systemic therapy in intermediate-stage HCC led to the inclusion in some recent guidelines of systemic therapy as the first choice of treatment in TACE-unsuitable patients with intermediate-stage HCC. Despite these recommendations, no randomized clinical trial has been published comparing LRT with TACE/TARE versus systemic therapy in patients with intermediate-stage HCC and high tumor burden. Methods: REPLACE is a phase III, multicenter, randomized, open-label trial that will compare the efficacy and safety of LRT with TACE/TARE versus systemic therapy, for the first-line treatment of intermediate-stage HCC with beyond up-to-7 criteria. Eligible participants will be randomized 1:1 to receive regorafenib (90 mg orally q.d. on days 1 to 21 of a 4-week cycle), and pembrolizumab (400 mg i.v. on day 1 of a 6-week cycle) or LRT with TACE or TARE, and will be stratified according to geographic region (Asia vs. non-Asia), ECOG Performance Status (0 vs 1) and Albumin-Bilirubin (ALBI) grade (1 vs 2). Patients must have intermediate-stage HCC with beyond up-to-seven criteria (Up-to-7 criteria = largest tumor diameter (cm) + number of tumors ≤7), measurable disease per RECIST 1.1, disease not amenable to curative treatment but amenable to LRT with TACE or TARE, no prior systemic or LRT for HCC, except for successful resection and/or ablation completed ≥ 6 months prior to randomization. Patients will be treated until progressive disease, unacceptable toxicity, or other treatment discontinuation criteria is met. The primary endpoint is progression free survival (PFS), assessed locally by the Investigator using mRECIST for HCC. Secondary endpoints include PFS assessed locally by the Investigator using RECIST 1.1; PFS centrally assessed using mRECIST and RECIST 1.1; overall survival; overall response rate according to RECIST v.1.1 and mRECIST based on the Investigator’s and central assessment; time to unTACEable progression; duration of response; safety and tolerability of the trial treatments, and patient reported outcomes for health-related quality of life. The estimated enrollment is 496 patients from approximately 14 countries. Recruitment started in October 2023 and is currently ongoing. Clinical trial information: NCT04777851 .

Perioperative therapy for resectable and borderline resectable pancreatic adenocarcinoma: An AGICC clinical trial.

4175 Background: Patients (pts) with pancreatic adenocarcinoma (PDAC) who are candidates for surgery are anatomically segregated into two groups: those with resectable tumors (R-PDAC), and those with borderline resectable tumors (BR-PDAC). For each group, complete surgical resection with no visible or microscopic disease left behind (R0 resection) is generally accepted as the path to cure. Neoadjuvant therapy (NAT) has been used to improve the R0 resection rate. However, the optimal role and type of NAT that will improve R0 resection rate and overall survival (OS) remains controversial. The Academic Gastrointestinal Cancer Consortium (AGICC) evaluated a perioperative strategy with combination chemotherapy and preoperative stereotactic radiation therapy (SBRT) to improve the R0 resection rate. Methods: This prospective, multicenter open label, single arm phase 2 clinical trial conducted among 5 member AGICC institutions enrolled pts with R-PDAC and BR-PDAC. Treatment included 3 cycles of gemcitabine (1000mg/m2) and nab-paclitaxel (125 mg/m2) (GEM/NAB) on days 1, 8 and 15 of a 28-day cycle prior to SBRT (33Gy: 6.6Gy daily x 5) followed by surgery and 3 cycles of adjuvant GEM/NAB. Accrual goal was 20 R-PDAC and 30 BR-PDAC pts selected by central radiology review. Primary objective was to estimate the R0 resection rate for each cohort. Secondary objectives included safety and tolerability of neoadjuvant treatment and OS. Results: Eighty-six pts signed consent and after radiologic screening, 20 R-PDAC patients and 29 BR-PDAC patients were found eligible to begin treatment. One R-PDAC and two BR-PDAC pts did not initiate therapy. 14 (70%) and 19 (66%) R-PDAC and BR-PDAC pts, respectively, completed all neoadjuvant chemotherapy.14 R-PDAC (70%) and 17 BR-PDAC (59%) pts completed SBRT. 11 R-PDAC pts (55%) and 11 (38%) BR-PDAC, underwent surgery. 8 R-PDAC pts (40%) had an R0 resection. One R-PDAC pt had a complete pathologic response (pCR). 8 BR-PDAC pts (28%) had an R0 resection. 19% (3/16) pts undergoing an R0 resection are alive (47-73+ mos). 16 pts (32%) had at least one grade ≥ 3 non-hematologic adverse event (AE); 25 patients (51%) had at least one grade ≥ 3 hematologic AE. 8 pts, 4 R-PDAC and 4 BR-PDAC were hospitalized prior to surgery. One pt (2%) died during NAT. There were no deaths due to surgery. Conclusions: R0 resection rates and survival in R-PDAC and BR-PDAC were low despite a perioperative approach of systemic therapy and SBRT. The lack of survival benefit of GEM/NAB as an adjuvant regimen, as well as SBRT pre-operatively (both shown in studies subsequent to this one) may explain the disappointing results. While an R0 resection for localized PDAC is recognized as essential, our results demonstrate that an R0 resection is not sufficient to cure the majority of PDAC pts who receive NAT with GEM/NAB + SBRT. Future NAT therapy trials should aim to markedly improve the pCR rates associated with R0 resection. Clinical trial information: NCT02723331 .

Evaluation of drug tolerability as a function of toxicity and quality of life in patients enrolled on I-SPY2.

11113 Background: Patient-reported outcomes (PROs) are valuable for understanding treatment tolerability and toxicity. I-SPY2 is a phase-II neoadjuvant clinical trial for breast cancer with electronic PROs and quality of life (QOL) assessments. We sought to understand how well the GP5 self-reported tolerability item reflected toxicity burden and QOL during treatment and follow-up in I-SPY 2 participants. Methods: Our study included 306 patients who completed the FACIT Item GP5 and answered PROMIS surveys at two or more timepoints. Analysis timepoints included screening (SC), inter-regimen (IR), pre-surgery (PS), 1-month post-surgery (FU1), and 6-months post-surgery (FU2). Symptoms were assessed weekly using PRO-CTCAE and CTCAEv4.0. QOL was evaluated using PROMIS. The GP5: “I am bothered by side effects of treatment,” was used to estimate tolerability, where worse tolerability is a higher score. Odds ratios, Spearman correlation, and regularized multi-variate regression were used to evaluate the associations between individual symptoms and adverse events with GP5 scores. Results: Demographic information was available for 243 of the 306 (70.2%) participants (median age=47,73.7% white). In the 306, tolerability scores worsened over study treatment, with a maximum mean score of 1.71 at Cycle 11. Tolerability improved after treatment cessation at FU1(1.09). Mean tolerability at week 6 was 1.53. The only clinical factor that was associated with early change in tolerability (week 6 to PS) was age &gt;50 (mean score ranged from 1.55-1.70 vs 1.29-1.45 (age&lt;50), p&lt;0.05). PRO-CTCAE and GP5 correlative analysis suggested that higher grade abdominal pain, decreased appetite, dizziness and blurry vision significantly associated with higher GP5 scores at multiple timepoints (p&lt;0.05). Symptoms not associated with tolerability were nail loss, acne, hair loss, and rash (p&gt;0.05). Additionally, the total number of low-grade (mild to moderate) symptoms a patient experienced during study treatment was significantly correlated to poor tolerability (p&lt;0.00001). Among patients with CTCAE data, 9% had adrenal insufficiency, and higher GP5 was found across all study timepoints in those with (compared to without) adrenal insufficiency (mean GP5 = [1.7-1.9] vs [1.3-1.5] respectively). Similarly, among patients with neuropathy (14%), higher GP5 scores were reported across all study timepoints (mean GP5 = [1.8-2.3] vs [1.3-1.5] respectively). Higher GP5 scores during treatment were correlated with higher fatigue scores at PS and FU1 (p&lt;0.02 and p&lt;0.001) and lower physical functioning at PS (p&lt;0.01). Conclusions: TheGP5 measure is associated with self-reported symptoms, higher grade adverse events and quality of life scores. Furthermore, greater accumulation of lower grade symptoms can lead to poor tolerability. The single measure GP5 composite score reflects multiple components of treatment toxicity.

Adherence to adjuvant hormone therapy in hormone-sensitive breast cancer: Insights from the Medical Oncology Department at Hassan II University Hospital, Morocco.

e12505 Background: Adjuvant endocrine therapy (AET) improves long-term survival for hormone-sensitive breast cancer; However, suboptimal adherence is prevalent, with many women failing to follow prescribed dosage and frequency. Long-term adherence patterns to AET are poorly understood. Additionally, there is a lack of data regarding the adherence to AET among Moroccan women and the factors that may influence it. Objectives: The primary objective of the study was to assess the adherence rate to AET in patients with HR-positive early breast cancer being treated at Hassan II University Hospital of Fez, Morocco. Secondary objectives included determining factors associated with poor adherence and assessing the adverse events associated with AET and their prevalence. Methods: We conducted a cross-sectional study involving 335 breast cancer patients undergoing AET. Eligible patients, who had received at least one dispensing of AET, participated in the study through a direct questionnaire survey after providing signed consent. The questionnaire comprised sections covering patient demographics, clinical data (stage, type of AET, duration of therapy), side effects or symptoms related to AET, other factors that may impact adherence. Adherence to AET was assessed at three points of measurement: 1 year, 3 years, and ≥ 5 years after the initiation of therapy. The study was carried out with respect to the Moroccan regulation in effect. Results: The study included 335 cases with an average age of 54 years. Participants were predominantly illiterate (62%) and post-menopausal (50.7%). Most were classified as stage II UICC (53.5%). Mastectomy was performed in the majority (74%). Neo(adjuvant) CMT was given to 79.4%, and adjuvant radiotherapy to 86.9%. Tamoxifen was administered to 55.4%, and aromatase inhibitors to 44.6%. Medical castration was associated with 12.5%, and 35 patients switched AET over time. Only 12.8% exceeded 5 years of AET during recruitment. Adherence assessment revealed an overall adherence rate of 53.4%. Notably, 67.2% claimed never to forget their medication, and about 20% temporarily stopped it, primarily due to lack of information. Most participants used a reminder strategy, notably alarms (43.3%). Treatment tolerance varied, with hot flushes and arthralgia being predominant side effects. Statistical analyses found a significant link between treatment lasting over 5 years and non-adherence (p = 0.003). However, the use of an alarm as a reminder strategy strengthened adherence (p = 0.021). No statistically significant differences were noted in other variables. Conclusions: Despite the benefits, ensuring adjuvant hormone therapy adherence is challenging. Our analysis, estimating a 53.4% global adherence, found that only treatment duration and recall strategy significantly correlated with adherence.

Development and validation of point-of-care mobile solution to guide the diagnosis of malnutrition: A multicenter, prospective cohort study.

11042 Background: Malnutrition has negative effects on patients with chronic diseases, leading to reduced treatment tolerance, increased risk of clinical complications, and even death. This research was aimed to develop a point-of-care program based on facial features to screen malnourished inpatient patients. Methods: In this prospective, multicenter, cohort study, we retrieved facial photograph and malnutrition screening scales from 4 different hospitals. We utilized a variety of machine learning models to explore whether the ocular area could serve as an enhanced region for facial recognition nutrition. Last, we utilized a facial area segmentation and weighted approach to retain the information of full-face features using a BP neural network and validated using Delong-test, IDI-test, and NRI-test. Overall, 619 inpatients’ facial photographs and their corresponding nutrition screening questionnaires were used to train, validate and test the machine learning model. Results: The Pearson correlation analysis showed a significant correlation (p&lt;0.05) between the two questionnaires in all groups. The average AUC obtained from the five-fold cross-validation set was 0.886 (CI 0.843-0.930), 0.834 (CI 0.764-0.904), and 0.927 (CI 0.899-0.955) for the Cancer Inpatient Group, Other Inpatient Group, and All Inpatient Group, respectively, with the corresponding AUC obtained from the external validation set being 0.860 (CI 0.817-0.904), 0.843 (CI 0.796-0.889), and 0.887 (CI 0.829-0.944). Conclusions: The facial photograph-based point of-care mobile solution can screen malnutrition with good accuracy, showing its potential for screening malnutrition in inpatients in the hospital in different types of diseases.

Evidence-based clinical recommendations for hypofractionated radiotherapy: exploring efficacy and safety - Part 2. Lung (non-small cell lung cancer).

Several recent studies have investigated the use of hypofractionated radiotherapy (HFRT) for various cancers. However, HFRT for non-small cell lung cancer (NSCLC) with or without concurrent chemotherapy is not yet widely used because of concerns about serious side effects and the lack of evidence for improved treatment results. Investigations of HFRT with concurrent chemotherapy in NSCLC have usually been performed in single-arm studies and with a small number of patients, so there are not yet sufficient data. Therefore, the Korean Society for Radiation Oncology Practice Guidelines Committee planned this review article to summarize the evidence on HFRT so far and provide it to radiation oncology clinicians. In summary, HFRT has demonstrated promising results, and the reviewed data support its feasibility and comparable efficacy for the treatment of locally advanced NSCLC. The incidence and severity of esophageal toxicity have been identified as major concerns, particularly when treating large fraction sizes. Strategies, such as esophagus-sparing techniques, image guidance, and dose constraints, may help mitigate this problem and improve treatment tolerability. Continued research and clinical trials are essential to refine treatment strategies, identify optimal patient selection criteria, and enhance therapeutic outcomes.

Datopotamab deruxtecan (Dato-DXd) vs chemotherapy (CT) in previously treated inoperable or metastatic hormone receptor-positive, HER2-negative (HR+/HER2–) breast cancer (BC): Patient-reported outcomes (PROs) from the TROPION-Breast01 study.

1006 Background: In the primary analysis of the Phase 3 TROPION-Breast01 study (NCT05104866), Dato-DXd showed a statistically significant and clinically meaningful improvement in progression-free survival vs investigator’s choice of CT (ICC) (HR 0.63 [95% CI 0.52‒0.76]; p&lt;0.0001) (Bardia et al, ESMO 2023). Here we report PROs from TROPION-Breast01. Methods: Patients with inoperable or metastatic HR+/HER2‒ BC, with disease progression on endocrine therapy and for whom endocrine therapy was unsuitable and who had received 1‒2 prior lines of systemic CT, were randomized 1:1 to Dato-DXd (6 mg/kg Q3W, n=365) or ICC (eribulin/vinorelbine/capecitabine/gemcitabine, n=367). PROs were measured at prespecified timepoints, including secondary PRO endpoints of time to deterioration (TTD) in global health status (GHS)/QoL, physical functioning, and pain based on EORTC QLQ-C30, and exploratory PRO endpoints based on additional questionnaires. Results: PRO questionnaire compliance was 82.5% at baseline in both arms and remained similar across arms over time. TTD was delayed in Dato-DXd vs ICC arms for all secondary endpoints. In an analysis of time to first deterioration (primary analysis), median TTD (HR [95% CI]) in GHS/QoL was 3.4 vs 2.1 months (0.85 [0.68–1.06]), physical functioning was 5.6 vs 3.5 months (0.77 [0.61–0.99]), and pain was 3.5 vs 2.8 months (0.85 [0.68–1.07]); in an analysis of time to confirmed deterioration (sensitivity analysis), median TTD in GHS/QoL was 9.0 vs 4.8 months (0.76 [0.58–0.98]), physical functioning was 12.5 vs 6.2 months (0.77 [0.59–1.01]), and pain was 9.0 vs 5.5 months (0.72 [0.55–0.94]). The Table shows TTD in other selected functioning and symptom scales from EORTC. Patient-reported symptomatic AEs (measured by PRO-CTCAE and EORTC) were generally consistent with clinician-reported safety data, and patient-reported treatment tolerability (measured by PGI-TT) was comparable between arms. Conclusions: In TROPION-Breast01, TTD was delayed in the Dato-DXd vs ICC arms for GHS/QoL, physical functioning, pain, and most other symptoms and functioning scales. PRO data complement the improvement in efficacy and manageable safety profile demonstrated with Dato-DXd vs ICC in the primary analysis, supporting Dato-DXd as a potential new, well tolerated therapeutic option in this setting. Clinical trial information: NCT05104866 . [Table: see text]