Tolerability Of Treatment Research Articles

Abstract PO3-12-03: SAFETY AND TOLERABILITY OF SHOCKWAVE THERAPY FOR TREATMENT OF BREAST CANCER-RELATED LYMPHEDEMA: A SYSTEMATIC REVIEW

Abstract Introduction: Breast cancer is currently the most common malignancy among women, after non-melanoma skin cancer. Upper limb lymphedema is the most feared complication of breast cancer treatment. Currently, the approach described in the literature as the most effective for the treatment of lymphedema is Complex Physical Therapy. In the search for more efficient therapeutic actions, Shockwave Therapy emerges as an alternative in the treatment of upper limb lymphedema secondary to breast cancer. Objective: to systematically review the available literature and verify the safety, tolerance and efficacy of using Shockwave Therapy (ESWT) in the treatment of upper limb lymphedema secondary to breast cancer. Methods: The following databases were used: PubMed; PEDro, The Cochrane Library, EMBASE, Web of science and Scopus and through manual search of articles. The PICO research method was adopted, and the descriptors adjusted according to the respective database. This study was registered in PROSPERO: CRD42020209588. Results: Combined searches, including reference lists, manual searches, and database searches, yielded 64 articles, of which 35 articles were duplicates, 23 studies were excluded by title, abstract, or full reading. Six full-text articles were selected. Of these, only 3 randomized clinical trials and 3 non-randomized clinical trials met all established inclusion criteria and were analyzed in this systematic review. Two more RCTs were added by manual search of references from other articles. None of the studies found had safety and tolerability as their primary objective, and one reported transient redness with the use of the device. Shockwave Therapy, combined with other resources, can significantly improve lymphedema volume and shoulder range of motion, but there is not enough evidence to support the use of ESWT as a substitute for complex physical therapy (CPT). Final considerations: There is evidence that it can improve ROM and upper limb volume when used in association with CPT, which is the gold standard for the treatment of lymphedema. Keywords: Lymphedema, Breast Cancer, Extracorporeal Shockwave Therapy. Citation Format: Patricia Lima Ventura, Cinira Haddad, Afonso Nazário, Gil Facina, Vanessa Sanvido, Amanda Estevao, Samantha Lopes de Almeida Rizzi. SAFETY AND TOLERABILITY OF SHOCKWAVE THERAPY FOR TREATMENT OF BREAST CANCER-RELATED LYMPHEDEMA: A SYSTEMATIC REVIEW [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-12-03.

Abstract PO3-05-12: Randomized Phase 2 of Bria-IMT, an Allogenic Human Cell Line with Antigen Presenting Activity, in Heavily Pretreated Metastatic Breast Cancer

Abstract Introduction Despite progress in MBC, too many continue to succumb due to treatment resistance or intolerance. SV-BR-1-GM is an allogenic human breast cancer cell line with antigen presenting cell activity designed to overcome the immune-suppressive tumor microenvironment while being acceptable to extensively pretreated contemporary MBC patients. We report interim exploratory analysis of the ongoing RCT of the Bria-IMT regimens. Methods An interim exploratory analysis using preliminary partially available evaluable data of the ongoing prospective, randomized phase 2 (NCT03328026; 2018-present) of Bria-IMT (irradiated SV-BR-1-GM) with a PD-1check point inhibitor (CPI) every 3 weeks (25 patients dosed to date). Both regimens include cyclophosphamide 300 mg/m2 48-72 hours prior to intradermal Bria-IMT (~20 x 106 cells) followed by interferon-alpha at the inoculation sites 2 days later. The control arm used the original sequence with simultaneous start of Bria-IMT and CPI in cycle 1. The experimental arm started CPI in cycle 2 after the 2nd inoculation. Candida skin test was performed before cycle 1 to determine anergy status while delayed-type hypersensitivity skin test (DTH), defined as >5mm erythema & induration, was done at every cycle by intradermal injection of a small test dose of Bria-IMT prior to full dose inoculation. Results Median age: 58 (range 37-81); median prior therapies: 8 lines (range 4-18); 89% were grade 2/3 (n=18); 68% hormone receptor positive; 61% HER2 negative, 33% HER2 low, and 6% HER2 high; 33% triple negative. Overall, 53% of subjects had a clinical benefit as best response by BICR, PI or target lesion measurement. The two treatment arms were similar with a trend showing longer median durations on therapy (mDOT) of 3.7 mo in the experimental delayed CPI arm compared with mDOT = 2.9 for original sequence control arm. 47% of patients were anergic to candida. Among all anergic subjects, the mDOT was 3.5 compared to 2.5 mo for non-anergic patients. However, among anergic subjects, the alternative treatment arm had a lower risk of treatment discontinuation (improved HR) with mDOT of 3.7 compared to the 3.3 mo mDOT of the original treatment. 50% of anergic subjects eventually developed DTH to SV-BR-1-GM. mDOT was 4.0 mo for DTH+ pts vs 3.0 mo for those who did not mount DTH. Median OS was not yet reached; mean OS was higher in non-anergic vs anergic pts. Among those who developed an inoculation site reaction to Bria-IMT, OS was greater than for those who did not. Time on the Bria-IMT regimen exceeded the time on penultimate treatment in 22% of subjects while 33% of subjects with prior CPI use exceeded last therapy. AEs were mild with 28% of subjects (n=7) having > grade 3 events. The most common grade 3+ AE was lipase increase (n=3). One subject with encouraging changes in peripheral blood tumor markers and CTCs completed a PET study using Zr-89 crefmirlimab berdoxam, a zirconium-89 labelled truncated antibody specific to human CD8α (CD8 Immuno-PET) and demonstrated increased uptake in some metastatic lesions and draining lymph nodes. Updated results will be provided at the meeting. Conclusion Sequencing of CPI with Bria-IMT is associated with differential clinical outcome trends but not statistically significant in this interim preliminary exploratory analysis regardless of prior CPI use. Bria-IMT is immunogenic with clinical benefit demonstrated for both treatment schedules among patients with inducible DTH reactions. Patients who develop an immune response to Bria-IMT had an increase in OS compared to those who did not. The nodal localization of CD8+ cells on PET may indicate a systemic activation of CD8 positive lymphoid cells. It also provides support that the Bria-IMT + CPI combination immune-based therapy can result in an increase of CD8+ tumor infiltrating lymphocytes in breast cancer metastatic sites. These preliminary results will be evaluated in the ongoing randomized phase 3 pivotal registrational trial. Citation Format: Carmen Calfa, Chaitali Nangia, Minal Barve, John Knecht, Jarrod Holmes, Kendrith Roland, Ralph Boccia, Frances Valdes-Albini, Zach Gostout, Mingjin Chang, William Williams, Charles Wiseman, Bonnie Guerin, Shaker Dakhil, Giuseppe Del Priore, Saranya Chumsri. Randomized Phase 2 of Bria-IMT, an Allogenic Human Cell Line with Antigen Presenting Activity, in Heavily Pretreated Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-05-12.

Abstract PO1-20-02: MiRaDor: A proof-of-concept study of treatment efficacy by monitoring Minimal Residual Disease (MRD) using circulating tumor DNA (ctDNA) in hormone receptor-positive/HER2-negative (HR+/HER2-) early breast cancer (EBC)

Abstract Background: Detection of MRD through ctDNA has been consistently associated with high risk of relapse. Longitudinal evaluation of ctDNA to monitor MRD is a minimally invasive tool that may predict disease recurrence and treatment response. MiRaDor aims to improve the clinical utility of ctDNA and understand its applicability in high-risk, HR+/HER2- EBC patients (pts). Trial Design: MiRaDor (NCT05708235) is a multicenter, open-label, non-comparative, phase II trial. Selection criteria include pts: a) with HR+/HER2- EBC at high risk of relapse, b) on adjuvant treatment with endocrine therapy (ET) for at least 2 years with 3 additional years of planned ET, c) no prior treatment with cyclin-dependent kinases 4/6 inhibitors or fulvestrant, and d) had surgery for their primary BC in the last 5 years. The trial has two phases, ctDNA surveillance (n=1260) and treatment (n=40-60). The surveillance phase will analyze ctDNA, with the FoundationOne® Tracker, every 3 months for the 1st year and every 6 months thereafter until ctDNA detection, end of the adjuvant ET, or completion of treatment phase accrual. Pts with positive ctDNA without radiological disease progression (PD) will be allocated to 1 of the treatment arms (n=10): A) standard ET; B) giredestrant; C) giredestrant + abemaciclib; or D) giredestrant + inavolisib (if PIK3CA mutation). Treatment will continue until evidence of PD, physician’s and/or patient’s decision, or until the end of study treatment (abemaciclib/inavolisib for up to 2 years, 5 years for ET). Tumor assessments will be periodically performed to rule out radiological PD. The primary objective is to evaluate the rate of pts with at least 90% decrease or clearance in ctDNA after 3 months of treatment. Key secondary objectives include the proportion of pts with 90% decrease in baseline ctDNA at 6, 9, and 12 months, 70%, and 50% decrease in ctDNA at 3, 6, 9, and 12 months, and treatment safety and tolerability. A cohort expansion up to 20 pts in 1 or 2 arms will occur if at 3 months a 90% ctDNA decrease is observed in at least 30% of pts and if, after 3 additional months, a 90% ctDNA decrease is maintained in at least 20% of pts. Citation Format: Antonio Llombart-Cussac, José Manuel Pérez-García, María Gion, Daniel Alcalá-López, Janet Fazal-Salom, Alexandros Lazaris, Mario Mancino, Eileen Shimizu, Susana Victorino, Rui Rui Zhang, Zuzana Machackova, Frauke Schimmoller, Matthew Wongchenko, Joseph Gligorov, Peter Schmid, Javier Cortés. MiRaDor: A proof-of-concept study of treatment efficacy by monitoring Minimal Residual Disease (MRD) using circulating tumor DNA (ctDNA) in hormone receptor-positive/HER2-negative (HR+/HER2-) early breast cancer (EBC) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-20-02.

Abstract PO5-03-09: Concurrent versus sequential use of adjuvant capecitabine and radiation in patients with triple-negative breast cancer with residual disease: A retrospective review

Abstract Background: The CREATE-X trial demonstrated benefit of adjuvant capecitabine for patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy and surgery. In clinical practice however, physician discretion determines the sequence of capecitabine relative to radiation therapy (RT), as well as the treatment dose. Therefore, our study aimed to assess the treatment patterns and tolerance of capecitabine and RT in patients with residual TNBC at our institution after publication of the CREATE-X study. Methods: This was a retrospective IRB-approved study that included patients with TNBC who had residual disease following neoadjuvant chemotherapy and surgery and received both adjuvant loco-regional RT and capecitabine at our institution between July 1, 2017 and June 30, 2021. Patient characteristics and treatment regimens were abstracted from medical charts. For this study, we defined optimally-delivered capecitabine to be a starting dose of 1250 mg/m2 twice per day on days 1-14 every 3 weeks as per the CREATE-X trial, and all planned cycles completed without dose reductions or discontinuation. RT was defined as optimally delivered when patients completed the prescribed dose without a treatment break of > 1 week or discontinuation of planned RT. We used descriptive statistics to report our observations. Results: Thirty-four patients met our eligibility criteria. The median age at diagnosis was 56 years (range: 30-77 years) and the median follow up time was 48 months. Of the 27 patients who received sequential RT and capecitabine, the median starting dose of capecitabine was 1000 mg/m2. Of the 7 patients who received concomitant RT and capecitabine, the median starting dose during RT was 800 mg/m2; after completion of RT, patients completed 6 additional cycles of capecitabine at a median dose of 1000 mg/m2. We observed a greater residual breast tumor burden in patients prescribed concomitant RT and capecitabine; 71.4% were ypT2/T3 compared to only 18.5% ypT2/T3 in sequentially treated patients (OR 11.0; 95% CI, 1.64 to 73.97; p=0.05). There was no significant difference in the positive lymph node status between the 2 groups (42.9% and 40.7%, respectively). A median RT dose of 50 Gy in 25 fractions was delivered in both schedules. No patients discontinued RT due to intolerance. In the 27 sequentially treated patients, the majority (73%) received RT before capecitabine. Among these, 14 patients (51.9%) required a dose reduction and 6 patients (22.2%) discontinued capecitabine due to intolerance. Of the 7 patients receiving concomitant RT and capecitabine, 2 patients (28.5%) discontinued capecitabine due to intolerance (one during RT and one following completion of RT). The concomitant RT and capecitabine regimen was not associated with higher odds of prematurely discontinuing capecitabine compared to the sequential schedule (OR 1.15; 95% CI, 0.18 to 7.34). Conclusion: In this study, most patients received a sequential schedule and those with a higher residual disease burden were more likely to be prescribed concomitant RT and capecitabine. The starting dose of capecitabine in both schedules was lower than the starting dose in the CREATE X trial but consistent with the practice standard in the US. Our early experience did not demonstrate any signal to suggest a difference in the tolerance of capecitabine administered sequentially or concurrently. Further studies are needed to evaluate the optimal sequence of RT and capecitabine in the adjuvant setting. Citation Format: Catherine Yu, Alaina Kessler, Theresa Shao, Sarah Cate, Paula Klein, Manjeet Chadha. Concurrent versus sequential use of adjuvant capecitabine and radiation in patients with triple-negative breast cancer with residual disease: A retrospective review [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-09.

Abstract PO4-01-06: HER2-positive early breast cancer (EBC): treatment, toxicities and outcomes in a retrospective cohort of elderly patients (pts)

Abstract Background: Approximately one-third of breast cancer cases are diagnosed in women aged ≥70 years, presenting a considerable challenge to offer optimal treatment options. Ensuring appropriate care involves taking into account factors such as geriatric evaluation, comorbidities, and life expectancy. However, the lack of literature focusing on the elderly population makes it difficult to choose the correct treatment approach. Methods: We conducted a retrospective analysis including all elderly pts (≥70 years) with HER2-positive EBC treated at Vall d’Hebron hospital between 2016-2022. We evaluated treatment schemes, toxicities, and outcomes. Disease-free survival and overall survival from the time of diagnosis were assessed using Kaplan-Meier estimates. Results: Among 118 pts identified, the median age of diagnosis was 79.5 years (74-85). The main comorbidities were cardiovascular (82.2%), diabetes (19.5%), pulmonary (10.2%), and kidney diseases (9.3%). Stages (s) at diagnosis were: 16.8% sI, 56% sII and 24.8% sIII. 64.8% were hormone receptor-positive, 78.4% were HER2 3+ and 15.2% 2+ (ISH amplified). Median follow up was 29.1 months (m). Neoadjuvant (NA) treatment was administered to 60.2% of pts (n=71) of which 74.6% (n=53) received chemotherapy (CT) with taxanes (Tax) only (72.5%), anthracyclines (Ac)+Tax (17.6%) and Tax+carboplatin (7.8%). AntiHER2-agents were administered in 80.3% pts (n=57) of which 89.1% received trastuzumab and pertuzumab. 23.9% of pts (n=17) received exclusively aromatase inhibitor and 2.8% (n=2) associated double blockade. Overall, 87.3% (n=103) and 80% of NA treated pts (n=57) underwent surgery, specifically mastectomy in 37.9% and 46,6% pts in the NA group achieved a pathological complete response (pCR). 38.9% pts (n=46) were treated with surgery upfront. Adjuvant treatment (A) was administered to 82.9% (n=97) of pts, with 23.7% (n=23) receiving CT; primarily Tax (82.6%), Ac+Tax (13%) and Tax+carboplatin (4.3%). AntiHER2-agents were administered in 87.6% of pts (n=85). In the overall population, median disease-free survival (mDFS) and median overall survival (mOS) were 81.1m (95% CI 68.7-not reached [NR]) and 81.1m (95% CI 77.4-NR) respectively. In the pts who underwent surgery, mDFS was 81.1m (95% CI 68.7-NR), whereas mDFS in those who did not, was 17.6m (95% CI 13.1-NA). Pts who received antiHER2-agents in the A setting showed a mDFS of 81.1m (95% CI 81.1-NR) and mOS was NR (95% CI 81.1-NR) compared to those who did not, with a mDFS of 39.7m (95% CI 25.4-NR) and mOS of 77.4m (95% CI 25.4-NR). Toxicities were reported in 78.3% of pts (n=54) receiving NA treatment and in 54.7% of pts (n=52) in the A setting of which 25.9% (n=14) and 13.4% (n=7) corresponded to grade (G) 3 respectively. Hospitalization, treatment discontinuation and dose reduction were required in 13%, 25.9% and 29.6% of pts with NA treatment and in 23.1% and 19.6% of A pts respectively with no pts requiring hospitalization. NA/A main side effects included asthenia 70.4% (nG3=2)/67.3% (nG3=2), diarrhea 64.8% (nG3=4)/19.2% (no≥G3), neuropathy 27.8% (no ≥G3)/28.8% (nG3=1), nausea/vomiting 22.2%/3.9% (no ≥G3), infusion reaction 20.4% (nG3=2)/5.9% (no ≥G3) and cardiotoxicity in 3.8% (nG3=1)/7.8% (nG3=2). Conclusions: Our study provides real world data about the use of tailored treatments to reach a balance between treatment response and tolerance in an elderly population, with low discontinuation rates, satisfactory pCR rates and long-term results in patients treated with antiHER2-agents. It is crucial to evaluate risks and benefits of treatments in frail patients. Therefore, an oncogeriatric assessment program was started in 2021 to prospectively perform dedicated research in this population. Citation Format: Alejandra Rezqallah, Diego Gómez-Puerto, Ridhi Ranchor, Laia Joval-Ramentol, Lucia Sanz, Maria Borrell, Marcelo Alvarado-Cárdenas, Antonio San-José, Clara Morales Comas, Martin Espinosa-Bravo, Manuel Altabas, Esther Zamora, Carolina Ortiz, Patricia Gómez Pardo, Isabel Pimentel, Meritxell Bellet- Ezquerra, Mafalda Oliveira, Cristina Saura, Míriam Arumí, Santiago Escrivá-de-Romaní. HER2-positive early breast cancer (EBC): treatment, toxicities and outcomes in a retrospective cohort of elderly patients (pts) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-01-06.

Assessing a Suitable Radiotherapy Utilisation Benchmark for Older Patients With Head and Neck Cancer

AimsTo (i) determine the actual radiotherapy utilization (RTU) stratified by age, (ii) develop an age- and co-morbidity adjusted optimal RTU model and (iii) examine the tolerance and toxicity of treatment of older patients with head and neck cancer. Materials and methodsA retrospective cohort study based on New South Wales Cancer Registry records (2010–2014) linked to radiotherapy data (2010–2015) and admitted patient data (2008–2015) for patients diagnosed with head and neck cancer. We calculated the actual RTU, defined as the proportion of patients who received at least one course of radiotherapy within a year of diagnosis, by age group, including patients aged 80+ years. We also calculated the age and comorbidity-adjusted optimal RTU. For treatment tolerance, the radiotherapy dose for each age group and the completion rate for a seven week 70 Gray (Gy) course of curative intent radiotherapy were computed. The number of emergency department (ED) presentations were used as a surrogate measure of acute treatment toxicity for patients receiving 70 Gy. ResultsOf the 5966 patients diagnosed with head and neck cancer, 814 (13.6%) were aged 80+ years. For all age groups, the actual RTU was less than the optimal RTU. The age- and comorbidity-adjusted optimal RTU for patients aged 80+ was 52% (95% CI: 51%–53%), and the actual RTU was 40% (95% CI: 37%–44%). Only 4.4% of patients aged 80+ received 70 Gy, and the completion rate for a 70 Gy course of radiotherapy for these patients was 92%. The ED presentation rate was similar for all age groups. ConclusionThe actual RTU was less in the 80+ years patients and across all age groups. Fewer patients in the 80+ group received curative intent schedules compared to the actual RTU rate for younger age groups, despite similar rates of completion of curative intent radiotherapy and acute toxicity.

Safety and Tolerability of Online Adaptive High-Field Magnetic Resonance-Guided Radiotherapy.

In 2018, the first online adaptive magnetic resonance (MR)-guided radiotherapy (MRgRT) system using a 1.5-T MR-equipped linear accelerator (1.5-T MR-Linac) was clinically introduced. This system enables online adaptive radiotherapy, in which the radiation plan is adapted to size and shape changes of targets at each treatment session based on daily MR-visualized anatomy. To evaluate safety, tolerability, and technical feasibility of treatment with a 1.5-T MR-Linac, specifically focusing on the subset of patients treated with an online adaptive strategy (ie, the adapt-to-shape [ATS] approach). This cohort study included adults with solid tumors treated with a 1.5-T MR-Linac enrolled in Multi Outcome Evaluation for Radiation Therapy Using the MR-Linac (MOMENTUM), a large prospective international study of MRgRT between February 2019 and October 2021. Included were adults with solid tumors treated with a 1.5-T MR-Linac. Data were collected in Canada, Denmark, The Netherlands, United Kingdom, and the US. Data were analyzed in August 2023. All patients underwent MRgRT using a 1.5-T MR-Linac. Radiation prescriptions were consistent with institutional standards of care. Patterns of care, tolerability, and technical feasibility (ie, treatment completed as planned). Acute high-grade radiotherapy-related toxic effects (ie, grade 3 or higher toxic effects according to Common Terminology Criteria for Adverse Events version 5.0) occurring within the first 3 months after treatment delivery. In total, 1793 treatment courses (1772 patients) were included (median patient age, 69 years [range, 22-91 years]; 1384 male [77.2%]). Among 41 different treatment sites, common sites were prostate (745 [41.6%]), metastatic lymph nodes (233 [13.0%]), and brain (189 [10.5%]). ATS was used in 1050 courses (58.6%). MRgRT was completed as planned in 1720 treatment courses (95.9%). Patient withdrawal caused 5 patients (0.3%) to discontinue treatment. The incidence of radiotherapy-related grade 3 toxic effects was 1.4% (95% CI, 0.9%-2.0%) in the entire cohort and 0.4% (95% CI, 0.1%-1.0%) in the subset of patients treated with ATS. There were no radiotherapy-related grade 4 or 5 toxic effects. In this cohort study of patients treated on a 1.5-T MR-Linac, radiotherapy was safe and well tolerated. Online adaptation of the radiation plan at each treatment session to account for anatomic variations was associated with a low risk of acute grade 3 toxic effects.

Sex differences in the prognostic role of achieving target doses of heart failure medications: Data from the Swedish Heart Failure Registry.

Guidelines recommend target doses (TD) of heart failure (HF) with reduced ejection fraction (HFrEF) medications regardless of sex. Differences in pharmacokinetics and pharmacodynamics may explain heterogeneity in treatment response, adverse reactions, and tolerability issues across sexes. The aim of this study was to explore sex-based differences in the association between TD achievement and mortality/morbidity in HFrEF. Patients with HFrEF and HF duration ≥6 months registered in the Swedish HF Registry between May 2000 and December 2020 (follow-up until December 2021) were analysed. Treatments of interest were renin-angiotensin system inhibitors (RASI) or angiotensin receptor-neprilysin inhibitors (ARNI), and beta-blockers. Multivariable Cox regression models were performed to explore the risk of cardiovascular mortality or hospitalization for HF across dose categories in females versus males. A total of 17 912 patients were analysed (median age 77.0 years, interquartile range [IQR] 70.0-83.0), 29% were female. Over a median follow-up of 1.33 years (IQR 0.29-3.22), for RASI/ARNI there was no significant difference in outcome for females achieving 50-99% versus 100% of TD (hazard ratio 0.92, 95% confidence interval 0.83-1.03), whereas males showed a gradual lowering in risk together with the achievement of higher % of TD (p-interaction = 0.030). For beta-blockers the achievement of TD was associated with the lowest risk of outcome regardless of sex. Our findings suggest that females and males might differently benefit from the same dose of RASI/ARNI, and do represent a general call for randomized controlled trials to consider sex-specific up-titration schemes when testing HFrEF treatments in need of up-titration.

PREHABILITATION AND SUPPORTIVE CARE IN ONCOLOGY TREATMENT OF BREAST CANCER: PROACTIVE-B

INTRODUCTION & AIMS Neoadjuvant therapy has become standard treatment for patients with Stage II/III HER2 positive and triple negative breast cancer and in selected patients with locally advanced and borderline resectable high risk, luminal B breast cancer (1). Side effects such as fatigue, cardiotoxicity, neurotoxicity, anxiety, insomnia, vasomotor symptoms, gastrointestinal disturbance as well as a raft of immune-related adverse events, impact treatment tolerance, long term outcomes and quality of life. Post-treatment, many women increase body fat and decrease lean mass and develop metabolic syndrome (2) and accelerated cardiac aging (3). All of these are modifiable targets of exercise. The aim of this study was to determine if an early multi-modal supportive care program, designed through a qualitative study from consumers and healthcare professionals, can mitigate these side effects and improve chemotherapy completion, cardiometabolic, residual cancer burden (pCR) and surgical outcomes. METHODS This was a prospective, mixed-method, feasibility study that recruited 23 women receiving neoadjuvant therapy for breast cancer, combining qualitative and quantitative data collection and analysis. The supervised exercise intervention was designed to include aerobic interval, resistance and balance training twice/week, adapted for symptom burden in each session with relative training dose intensity calculated. An optional home program as also provided with therabands. Body composition, upper and lower body strength and cardiometabolic outcome measures were collected at baseline, end of first and second line of treatment and then 6 months post-surgery. RESULTS Full data will be completed in March 2024 to be presented. There was a high rate of complete pathological response (18/22). Currently, 13 participants have completed 6 month post-surgery assessments and preliminary analyses indicate increases in strength and maintenance of muscle mass during and after treatment. The program was found to be acceptable and feasible with high attendance and satisfaction ratings. The additional home program had poor uptake. Of interest to exercise physiologists was participant responses to cluster set training, how poorly rate of perceived exertion reflected training and strength testing loads, heart rate and blood pressure responses and treatment toxicities including cases of immunotherapy induced hepatitis. Many participants were stronger at the end of chemotherapy than before and reported that exercise gave them a sense of control. CONCLUSION Adapting exercise during neoadjuvant chemotherapy with additional supportive therapies for symptom management, improved physical and psychosocial functioning. The program was feasible and acceptable, with high satisfaction reported. Muscle mass can be maintained with supervised exercise training and maintained and 6 months after surgery.

Long-term effects of adjunctive eslicarbazepine acetate in adult Asian patients with refractory focal seizures: Post hoc analysis of a phase III trial.

A post hoc analysis of data from Asian patients included in the study BIA-2093-304 was conducted to evaluate the long-term safety/tolerability and efficacy of adjunctive eslicarbazepine acetate (ESL) in adult Asian patients with refractory focal seizures. Part I was a randomized controlled trial, in which patients received ESL (800 or 1200 mg once daily [QD]) or placebo, assessed over a 12-week maintenance period. Patients completing Part I could enter two open-label extension periods (Part II, 1 year; Part III, ≥2 years), during which all received ESL (400-1600 mg QD). Safety/tolerability was assessed by evaluating treatment-emergent adverse events (TEAEs). Efficacy assessments included responder and seizure freedom rates. The safety population included 125, 92, and 23 Asian patients in Parts I, II, and III, respectively. Incidence of ESL-related TEAEs was 61.3%, 45.7%, and 17.4% during Parts I, II, and III, respectively. ESL-related TEAEs (most commonly, dizziness, somnolence, and headache) were consistent with ESL's known safety profile. During Part I, responder rates were higher with ESL 800 (41.7%) and 1200 mg QD (44.4%) versus placebo (32.6%), although not statistically significant. Seizure freedom rates with ESL 800 (5.5%) and 1200 mg QD (11.1%) were also higher versus placebo (0%) (p < 0.05 for ESL 1200 mg QD versus placebo). At the end of Part II, responder and seizure freedom rates were 60.3% and 14.7%, respectively. In summary, adult Asian patients with refractory focal seizures were responsive to treatment with ESL as adjunctive therapy and generally showed treatment tolerance well for up to 3 years. No new/unexpected safety findings were observed.

A Comprehensive Review of Taxane Treatment in Breast Cancer: Clinical Perspectives and Toxicity Profiles.

Taxanes, such as paclitaxel and docetaxel, have transformed the landscape of breast cancer treatment, playing pivotal roles in chemotherapy protocols for both early-stage and advanced/metastatic diseases. While these agents have demonstrated remarkable efficacy in enhancing patient outcomes, they are also linked to a range of adverse effects that can impact treatment tolerability and quality of life. This comprehensive review offers an in-depth exploration of taxane therapy in breast cancer, with a focus on clinical perspectives and toxicity profiles. We delineate the mechanisms of action of taxanes, their clinical effectiveness across various breast cancer subtypes, and the prevalent adverse effects encountered in clinical practice. Moreover, we deliberate on strategies for mitigating taxane-associated toxicity and optimizing treatment selection and sequencing based on individual patient characteristics and therapeutic objectives. Finally, we underscore areas for future research and advancement, encompassing the development of novel formulations, the identification of predictive biomarkers for treatment response, and the exploration of combination therapies to bolster therapeutic outcomes. By amalgamating existing evidence and clinical insights, this review aims to apprise clinicians and researchers of the current status of taxane treatment in breast cancer and steer endeavors towardfurther enhancing patient care and outcomes.

Tolerability of Antihypertensive Medications: The Influence of Age.

Despite high prevalence of hypertension, few studies have analysed the adverse effects (AEs) of antihypertensive medications, especially in older patients. To investigate the prevalence and associated factors of antihypertensive-related AEs, focusing on the influence of age on treatment tolerability. We retrospectively investigated antihypertensive-related AEs in patients evaluated at the Hypertension Clinic of Careggi Hospital, Florence, Italy, between January 2017 and July 2020. Multivariable regression models were generated to analyse variables associated with AEs in the overall sample and in participants ≥75 years. Among 622 subjects (mean age 64.8 years, 51.4% female), the most frequently reported AEs were calcium-channel blockers (CCB)-related ankle swelling (26.8%) and ACEi-induced cough (15.1%). Ankle swelling was more common in older patients (35.7% vs 22.3%, p = 0.001; odds ratio [OR] 1.94, 95%CI 1.289-2.912) and was independently associated with Body Mass Index (BMI, adjOR 1.073) and angiotensin-receptor antagonists (adjOR 1.864). The association with BMI was confirmed in older patients (adjOR 1.134). ACEi-induced cough showed similar prevalence in younger and older patients (13.9% vs 15.6%, p = 0.634), being independently associated with female sex (adjOR 2.118), gastroesophageal reflux disease (GERD, adjOR 2.488) and SNRI therapy (adjOR 8.114). The association with GERD was confirmed in older patients (adjOR 3.238). CCB-related ankle swelling and ACEi-induced cough represent the most common antihypertensive-related AEs, also at old age. Older patients showed a two-fold increased risk of ankle swelling, that was also independently associated with BMI. ACEi-induced cough had similar prevalence at younger and old ages, being independently associated with GERD.

Primary care prescribing prior to lung cancer diagnosis (PPP-Lung): protocol for a systematic review

Background Lung cancer is the second most common cancer and the leading cause of cancer death worldwide. A significant reason for its high mortality is delayed diagnosis, with lung cancer typically diagnosed at an advanced stage. Previous research has shown that prescribing rates of certain medications increase in the 24 months preceding a cancer diagnosis. This suggests a potential opportunity for early diagnosis of lung cancer by the identification of high-risk patients based on the prescribing of medications associated with a subsequent lung cancer diagnosis. Our aim is to identify all prescribing events associated within an increased incidence of primary lung cancer in the subsequent 24 months. Methods We will conduct a systematic review, and, where possible, a meta-analysis, reporting the findings in accordance with the PRISMA reporting guideline. All peer-reviewed studies in the English language that quantitatively describe an association between prescribing data and lung cancer diagnosis using a control group will be eligible. Details regarding prescribing rate in the lung cancer group versus the control group will be extracted with study characteristics. Quality appraisal of studies, using ROBINS-E will be used for assessing risk of bias. For each drug studied, we will report prescribing rate ratios (PRRs) with 95% confidence intervals (CIs). A meta-analysis using a pooled estimate of PRRs, either by fixed or random-effect models, will be performed if possible. Conclusions This systematic review will summarise the evidence on drugs that, when prescribed, suggest the possibility of an as-yet-undiagnosed lung cancer. This research has the potential to impact clinical practice by informing targeted screening strategies and refining early detection protocols for this harmful disease. If achieved, this could increase the numbers of lung cancers diagnosed at an earlier stage, with consequent improvements to patients in terms of survival, treatment tolerability and quality of life.

P146 A phase II, randomised, double-blind, placebo-controlled trial exploring pharmacokinetics, safety and efficacy of intravenous factor XIII treatment in adults with systemic sclerosis

Abstract Background/Aims Systemic sclerosis (SSc) is a multi-system autoimmune disease with significant morbidity and mortality, and an unmet therapeutic need. The pathogenesis of SSc involves dysfunctional immune signalling, fibroblast behaviour and vascular development. Factor XIII (FXIII) is an enzyme involved in coagulation, and in wound healing where it promotes angiogenesis via inhibition of thrombospondin-1 (TSP-1). Therapeutic administration of FXIII in SSc is proposed to increase angiogenesis via suppression of TSP-1, which is known to be dysregulated in SSc. Previous preclinical and clinical studies suggest that therapeutic administration of factor XIII could improve vascular function in SSc. Methods Two interlinked clinical trials were conducted at a single centre. First, a single-dose open-label study was performed to assess the safety and pharmacokinetics of FXIII treatment in SSc. Eight adult patients with limited or diffuse SSc received a single dose of intravenous purified human FXIII, followed by a 6-week monitoring period. Second, a phase II, double-blind, randomised, placebo-controlled study was performed to investigate the safety and efficacy of factor XIII treatment in SSc. 18 adult patients with limited or diffuse SSc were randomised 2:1 to receive study intervention (intravenous purified human FXIII) or placebo (intravenous 0.9% sodium chloride solution). Safety endpoints were assessment of the safety and tolerability of FXIII treatment via review of adverse events, physical examination and monitoring of physiological function. Efficacy was explored as change in skin severity by modified Rodnan skin score (mRSS) at week 24 compared to baseline, and change in severity of Raynaud’s phenomenon, assessed by review of the Raynaud’s Condition Score (RCS) at week 24, compared to baseline. The study is registered with ClinicalTrials.gov (number NCT02551042). Results The main objective of the clinical trial was met by demonstrating that FXIII is safe and well tolerated in SSc. Pharmacokinetic analysis showed a predictable rise and fall in FXIII level following therapeutic administration, with the mean time taken for the FXIII level to return to within 10 IU/dL of the endogenous level being 16.6 days (SD 8.7). Adverse event and safety monitoring did not reveal any concerning pattern. Study intervention-related adverse events were self-resolving and tolerable. There was no statistically significant change in mRSS or RCS during the trial, but there was a trend towards improvement in RCS in the FXIII group (mean change in RCS of -1.2 (95% CI -2.26 to -0.14) in the FXIII group versus -0.83 (95% CI -3.44 to 1.77) in the placebo group). Conclusion Our results suggest that therapeutic strategies to modulate links between coagulation and tissue repair using FXIII are safe and feasible. Further studies with different patient populations and FXIII doses could investigate the role of FXIII in SSc further. Disclosure A. Leslie: Other; A.L. is an employee of GSK. S. Vigneswaran: None. K. Khan: None. V. Ong: None. C.P. Denton: Consultancies; C. D. has received consulting fees from Roche, Janssen, GlaxoSmithKline, Sanofi, Galapagos, Boehringer Ingelheim, and CSL Behring, and Acceleron. Grants/research support; C. D. has received research funding from CSL Behring, Horizon, Abbvie, and GlaxoSmithKline.

The Effectiveness and Tolerability of an Intensive Outpatient Trauma Treatment Program for Adolescents With PTSD

Following the promising effects of an intensive trauma treatment for adults, the question arises whether adolescents suffering from posttraumatic stress disorder (PTSD) can also benefit from a similar treatment program. The objective of this study was to assess the effectiveness and tolerability of an intensive trauma treatment program combining two evidence-based, trauma-focused therapies—prolonged exposure (PE) and eye movement desensitization and reprocessing (EMDR)—with psychoeducation and physical activity for adolescents suffering from PTSD in an outpatient clinic. We used a multiple-baseline study design. Fifteen adolescents aged 12–18 years old with aDiagnostic and Statistical Manual of Mental Disorders(5th ed.) diagnosis of PTSD were included. Participants were randomized to wait 2, 3, or 4 weeks between the start of baseline and the start of the intervention. In the 2-week intervention period, participants received daily PE, EMDR, and physical activity. The social network of adolescents was involved for support. PTSD symptoms and treatment tolerability were assessed daily. PTSD diagnosis was assessed at baseline and at 1 month and 3 months after completion of treatment. In addition, semistructured interviews were conducted after treatment to determine the tolerability. After treatment, we found a diagnostic PTSD remission of 58%–62% and a decrease in PTSD severity compared with baseline. The effects were maintained at 1-month and 3-month follow-ups. The dropout rate was 13%. Participants reported good treatment tolerability. This study provides initial evidence that an intensive outpatient trauma treatment including PE, EMDR therapy, psychoeducation, and physical activity is effective and tolerable for adolescents with PTSD and is associated with low dropout rates.

Meta-analysis: Persistence of advanced therapies in the treatment of inflammatory bowel disease.

The expanding options in advanced therapies for ulcerative colitis (UC) and Crohn's disease (CD) present challenges in treatment selection. Persistence analysis assesses drug durability in real-world settings, acting as a surrogate marker for medication efficacy and tolerance. Unlike traditional comparative studies, persistence analysis provides insights extending beyond the initial year of treatment. To provide real-world evidence on treatment effectiveness, tolerability and preferences of physicians and patients regarding various advanced therapies for IBD. We conducted a systematic review of observational studies up to March 2023 assessing advanced therapies' persistence in UC and CD. Advanced therapies under examination included infliximab, adalimumab, vedolizumab, ustekinumab, golimumab, certolizumab and tofacitinib. We pooled the persistence of each agent and conducted a meta-analysis to compare the persistence of newer agents with traditional TNF inhibitors (TNFi)-specifically infliximab and adalimumab. Among 63 observational studies, vedolizumab had the highest 1-year persistence in UC (73.8%, 95% CI: 70.0%-77.6%) and ustekinumab in CD (77.5%, 95% CI: 72.9%-82.1%). Compared to TNFi, vedolizumab demonstrated increased persistence with a relative risk (RR) of 1.30 (95% CI: 1.19-1.41) for UC and 1.14 (95% CI: 1.09-1.20) for CD at 1 year, while ustekinumab demonstrated a RR of 1.15 (95% CI: 1.07-1.23) for CD at 1 year. Vedolizumab exhibited sustained increased persistence in UC over 2 years compared to TNFi (RR: 1.33, 95% CI 1.14-1.54). This meta-analysis highlights the superior persistence of ustekinumab and vedolizumab over TNFi, and offers valuable insights for clinicians navigating the challenging landscape of UC and CD therapeutic choices.

Immunotherapy utilization patterns in patients with advanced cancer and autoimmune disease.

Immunotherapy has been shown to improve cancer survival, but there are no consensus guidelines to inform use in patients with both cancer and autoimmune disease (AD). We sought to examine immunotherapy utilization patterns between cancer patients with and without AD. This retrospective cohort study utilized data from a de-identified nationwide oncology database. Patients diagnosed with advanced melanoma, non-small cell lung cancer, and renal cell carcinoma were included. Outcomes of interest included first-line immunotherapy, overall immunotherapy, and number of immunotherapy cycles. We used logistic and Poisson regression models to examine associations between AD and immunotherapy utilization patterns. A total of 25,076 patients were included (796 with AD). Patients with AD were more likely to be female, White, receive care at academic centers, and have ECOG ≥ 3. Controlling for demographic and clinical variables, AD was associated with lower odds of receiving first-line (odds ratio [OR] = 0.68, 95% confidence interval [CI] 0.56-0.82) and overall (OR = 0.80, 95% CI 0.67-0.94) immunotherapy. Among patients who received at least one cycle of immunotherapy, there was no difference in mean number of cycles received between patients with and without AD (11.3 and 10.5 cycles respectively). The incident rate of immunotherapy cycles received for patients with AD was 1.03 times that of patients without AD (95% CI 1.01-1.06). Patients with AD were less likely to receive immunotherapy as first-line and overall therapy for treatment of their advanced cancer. However, among those who did receive at least one cycle of immunotherapy, patients with AD received a similar number of cycles compared to patients without AD. This not only indicates that AD is not an absolute contraindication for immunotherapy in clinical practice but may also demonstrate overall treatment tolerability and net benefit in patients with AD.

Teriflunomide in pediatric patients with relapsing multiple sclerosis: Open-label extension of TERIKIDS

Background: The double-blind TERIKIDS study demonstrated the efficacy and safety of teriflunomide. Objective: To evaluate the efficacy, safety, and tolerability of continuous teriflunomide treatment in the TERIKIDS open-label extension. Methods: In the double-blind period, children with relapsing MS were randomized to placebo or teriflunomide (14 mg adult-equivalent dose) for ⩽ 96 weeks. Participants received teriflunomide for ⩽ 192 weeks post-randomization in the open-label extension. Results: The mean age at screening was 14.6 years. For teriflunomide/teriflunomide versus placebo/teriflunomide, estimated clinical relapse risk was reduced by 38% (hazard ratio (HR) 0.62; 95% confidence interval (CI) 0.39–0.98; p = 0.11) and numbers of gadolinium-enhancing T1 and new/enlarging T2 lesions were reduced by 43% (relative risk (RR) 0.570; 95% CI 0.33–0.98; p = 0.043) and 49% (RR 0.511; 95% CI 0.34–0.76; p = 0.001), respectively, in the combined double-blind and open-label periods. There was a trend toward reduced risk of 24-week sustained disability progression for teriflunomide/teriflunomide versus placebo/teriflunomide (HR 0.47; 95% CI 0.23–0.96). During the open-label extension, incidences of safety-related discontinuations were 4.0% (teriflunomide/teriflunomide) and 13.5% (placebo/teriflunomide), including two children who developed pancreatitis in the teriflunomide/teriflunomide group. Conclusion: Teriflunomide reduced the long-term risk of focal inflammatory activity, with generally manageable tolerability and no new safety signals. Further evidence would strengthen clinical efficacy findings. ClinicalTrials.gov: NCT02201108.

Exploring the Language Used to Describe Older Patients at Multidisciplinary Cancer Conferences.

Older adults with cancer often present with distinct complexities that complicate their care, yet the language used to discuss their management at multidisciplinary cancer conferences (MCCs) remains poorly understood. A mixed methods study was conducted at a tertiary cancer centre in Toronto, Canada, where MCCs spanning five tumour sites were attended over six months. For presentations pertaining to a patient aged 75 or older, a standardized data collection form was used to record their demographic, cancer-related, and non-cancer-related information, as well as the presenter's specialty and training level. Descriptive statistics and thematic analysis were employed to explore MCC depictions of older patients (n = 75). Frailty status was explicitly mentioned in 20.0% of presentations, but discussions more frequently referenced comorbidity burden (50.7%), age (33.3%), and projected treatment tolerance (30.7%) as surrogate measures. None of the presentations included mentions of formal geriatric assessment (GA) or validated frailty tools; instead, presenters tended to feature select GA domains and subjective descriptions of appearance ("looks to be fit") or overall health ("relatively healthy"). In general, MCCs appeared to rely on age-focused language that may perpetuate ageism. Further work is needed to investigate how frailty and geriatric considerations can be objectively incorporated into discussions in geriatric oncology.

Real-world Evidence on Treatment Retention, Safety, and Tolerability of Edaravone in Canadian Patients with Amyotrophic Lateral Sclerosis (P5-11.012)

Real-world Evidence on Treatment Retention, Safety, and Tolerability of Edaravone in Canadian Patients with Amyotrophic Lateral Sclerosis (P5-11.012)