Mediators of a Mindfulness-Based Intervention for Younger Breast Cancer Survivors: Effects on Depressive Symptoms.

OBJECTIVE: Depression is associated with poor outcomes in breast cancer patients, with higher prevalence among younger women. While mindfulness-based interventions (MBIs) have demonstrated therapeutic effects, the mechanisms of intervention effects are poorly understood. We investigated whether rumination, self-kindness, intrusive thoughts about cancer, cancer-related worry, or meaning and peace mediated intervention effects of a MBI, Mindful Awareness Practices (MAPs), on depressive symptoms. Additionally, we explored the same variables as mediators of a psychoeducation program, Survivorship Education (SE). METHODS: Women diagnosed with Stage 0-III breast cancer at age < 50 were randomized to 6 weeks of MAPs (n = 85), SE (n = 81), or wait-list control (WLC; n = 81). During pre-, post-intervention, and 6-month follow-up (FU), we assessed depressive symptoms, rumination, self-kindness, intrusive thoughts, worry, and meaning and peace. RESULTS: MAPs and SE significantly reduced depressive symptoms at post-intervention, and reductions remained through 6-month FU for MAPs. Models revealed that reductions in rumination (ß = -0.68, 95% CI [-1.64, -0.07]) and intrusive thoughts (ß = 1.17, 95% CI [-2.17, -0.37]) and improvements in self-kindness (ß = -1.09, 95% CI [-2.37, -0.28]) and meaning and peace (ß = -1.09, 95% CI [-3.16, -0.56]) mediated MAPs' effects at all time points. Reductions in worry (ß = -1.34, 95% CI [-2.47, -0.45]) mediated effects at post-intervention only. Worry and intrusive thoughts mediated SE effects at post-intervention and 6-month FU, respectively. CONCLUSIONS: Findings identified depression-relevant mediators of MAPs' effects, expanding the understanding of MBI mechanisms. Results highlight pathways that could be leveraged to optimize intervention outcomes.

Type I interferons, inflammation, and fatigue in a longitudinal RNA study of women with breast cancer.

BACKGROUND: Fatigue is a common side effect of cancer and its treatment and is thought to be driven in part by activation of the proinflammatory cytokine network. However, the cellular and molecular underpinnings of cancer-related fatigue (CRF) have not been determined, nor have immune pathways beyond inflammation been carefully investigated. The goal of this study was to examine the association between CRF and activation of canonical proinflammatory gene regulation pathways and Type I interferon (IFN) signaling pathways in breast cancer patients during and after treatment. METHODS: Women diagnosed with early-stage breast cancer (n = 181) completed assessments before and after treatment with radiation and/or chemotherapy and at 6, 12, and 18-month post-treatment follow-ups. Assessments included self-reported fatigue (Multidimensional Fatigue Symptom Inventory - Short Form) and expression of pre-specified sets of Type I IFN and pro-inflammatory immune response genes determined from mRNA sequencing of PBMCs. Mixed effect linear models examined changes in fatigue and immune gene expression over time and tested the hypothesis that fatigue would be associated with increased expression of Type I IFN and inflammatory response genes. RESULTS: There were significant changes in fatigue and immune gene expression across the assessment period; all measures increased from pre- to post-treatment but showed diverging patterns over the follow-up, with declines in fatigue and persistent elevations in Type I IFN and proinflammatory gene expression. In mixed effect linear models, expression of Type I IFN response genes was elevated in association with fatigue across the assessment period, from pre-treatment to 18-month follow-up. In contrast, pro-inflammatory gene expression was associated with fatigue only at 6, 12, and 18-month follow-ups. Analyses controlling for changes in leukocyte subsets continued to show a significant association between fatigue and Type I IFN gene expression but reduced the time-dependent association with pro-inflammatory gene expression to non-significant. CONCLUSIONS: Results revealed unexpected complexity in the immune underpinnings of CRF and identify a novel role for IFN signaling as a robust contributor to this symptom before, during, and after treatment. Pro-inflammatory gene expression emerged as a predictor of fatigue later in the cancer trajectory, and that effect was primarily accounted for by a concurrent increase in monocyte prevalence.

Work Productivity Among Younger Breast Cancer Survivors: The Impact of Behavioral Interventions for Depression.

OBJECTIVES: The Pathways to Wellness randomized controlled trial found that 2 behavioral interventions, mindfulness awareness practices and survivorship education, reduced depressive symptoms in younger breast cancer survivors (BCSs) compared with wait-list control. This secondary analysis examines whether the interventions led to reduced loss of work productivity among younger BCSs and whether such reductions were mediated by reductions in depressive symptoms. METHODS: The Work Productivity and Activity Impairment scale was used to measure work productivity loss at 4 assessment time points. Correlates of productivity loss at enrollment were examined using multivariable linear regression. Differences in change over time in productivity loss between each intervention group and control were assessed using linear mixed models. Reduced depressive symptoms were tested as a mediator of reduced productivity loss. RESULTS: Of 247 trial participants, 199 were employed and included in the analyses. At enrollment, higher productivity loss was associated with chemotherapy receipt (P = .003), younger age (P = .021), more severe cognitive problems (P = .002), higher musculoskeletal pain severity (P = .002), more depressive symptoms (P = .016), and higher fatigue severity (P = .033). The mindfulness intervention led to significantly less productivity loss compared with control at all 3 postintervention assessment points (all P < .05), with about 54% of the effect mediated by reduction in depressive symptoms. Survivorship education was not associated with reduced loss of productivity. CONCLUSIONS: These findings suggest that addressing depressive symptoms through behavioral interventions, such as mindfulness, may mitigate impacts on work productivity in younger BCSs.

Overall side effect assessment of oxaliplatin toxicity in rectal cancer patients in NRG oncology/NSABP R04.

PURPOSE: Regulatory guidance suggests capturing patient-reported overall side effect impact in cancer trials. We examined whether the Functional Assessment of Cancer Therapy (FACT) GP5 item ("I am bothered by side effects of treatment") post-neoadjuvant chemotherapy/radiotherapy differed between oxaliplatin vs. non- oxaliplatin arms in the National Surgical Adjuvant Breast and Bowel Project (NSABP) R-04 trial of stage II-III rectal cancer patients. METHODS: The R-04 neoadjuvant trial compared local-regional tumor control between patients randomized to receive 5-fluorouracil or capecitabine with radiation, with or without oxaliplatin (4 treatment arms). Participants completed surveys at baseline and immediately after chemoradiotherapy. GP5 has a 5-point response scale: "Not at all" (0), "A little bit" (1), "Somewhat" (2), "Quite a bit" (3), and "Very much" (4). Logistic regression compared the odds of reporting moderate-high side effect impact (GP5 2-4) between patients receiving oxaliplatin or not after chemoradiotherapy, controlling for relevant patient characteristics. We examined associations between GP5 and other patient-reported outcomes reflecting side effects. RESULTS: Analyses were performed among 1132 study participants. Participants receiving oxaliplatin were 1.58 times (95% CI: 1.22-2.05) more likely to report moderate-high side effect bother at post-chemotherapy/radiation. In both arms, worse overall side effect impact was associated with patient-reported diarrhea, nausea, vomiting, and peripheral sensory neuropathy (p < 0.01 for all). CONCLUSION: This secondary analysis of R-04 found that GP5 distinguished between patients receiving oxaliplatin or not as part of their post-neoadjuvant chemoradiotherapy, adding patient-centric evidence on the reduced tolerability of oxaliplatin and demonstrating that GP5 is sensitive to known toxicity differences between treatments. CLINICALTRIALS: GOV: NCT00058474.

History and current status of the survivorship care program at the University of California, Los Angeles Jonsson Comprehensive Cancer Center (UCLA JCCC).

As one of the first comprehensive cancer centers to receive a designation from the National Cancer Institute, the Jonsson Comprehensive Cancer Center at UCLA Health has served as a leader in survivorship research for three decades. A clinical survivorship program for childhood cancer survivors was established in the early 2000s as this became a standard of care in pediatric oncology. However, it was not until receipt of external funding and the establishment of a Survivorship Center of Excellence in 2006 that clinical services were expanded to include adult cancer survivors, as well as survivorship care delivery research in the community and at affiliated clinical sites. When this funding ended, there was limited institutional support for expansion of the program, and so the clinical programs did not develop further. Recently, there has been renewed interest in obtaining Commission on Cancer accreditation, and this has prompted an institutional assessment of survivorship care to inform future activities for system-wide program development. As oncology care expands throughout a large regional health system network, the future survivorship program will need to serve as a common resource for the entire health system by providing a repository of specialized services and resources as well as standard processes and pathways for a cohesive approach to care. IMPLICATIONS FOR CANCER SURVIVORS: There are many challenges to development and sustainment of cancer survivorship programs, even in NCI-designated comprehensive cancers. As the delivery of cancer care services expands and becomes more integrated in large health care systems, innovative strategies are needed to ensure delivery of tailored care to cancer survivors through acute treatment and beyond.

Survivorship care in breast cancer: understanding implementation barriers through the lens of the Theoretical Domains Framework.

BACKGROUND: Breast cancer survivorship guidelines with specific recommendations on managing long-term effects are available, but uptake in clinical practice remains low. Using the lens of the Theoretical Domains Framework, we aimed to understand key factors in guideline-concordant management of long-term effects to inform future implementation efforts in clinical practice contexts. METHODS: As part of a broader survey of oncologists, a theory-guided questionnaire was developed. Oncologists were asked to report level of agreement with Theoretical Domains Framework-based statements, current usage and perceived value of survivorship resources, and frequency of managing long-term effects in routine care. Data analyses included psychometric assessment of the questionnaire, descriptive summaries of theoretical domains and survivorship resources, and multivariable logistic regression models. RESULTS: In total, 217 oncologists completed the Theoretical Domains Framework-based questionnaire; 54% of oncologists reported "always or almost always" evaluating physical effects at routine survivorship appointments, while 34% did so for psychosocial effects. In regression models, Environmental Context and Resources was the only theoretical domain found to be statistically significantly associated with "always or almost always" evaluating both physical (odds ratio = 0.29, 95% confidence interval = 0.09 to 0.80) and psychosocial (odds ratio = 0.09, 95% confidence interval = 0.02 to 0.35) effects. CONCLUSIONS: Findings support application of the Theoretical Domains Framework in understanding oncologists' behaviors and perceived barriers in managing long-term effects in breast cancer survivors. In future implementation efforts, this theory-informed approach can be used to target relevant domains and strategies focused on embedding guideline recommendations in the clinical context through structured resources and environmental supports.

When Will Real-World Data Fulfill Its Promise to Provide Timely Insights in Oncology?

Randomized trials provide high-quality, internally consistent data on selected clinical questions, but lack generalizability for the aging population who are most often diagnosed with cancer and have comorbid conditions that may affect the interpretation of treatment benefit. The need for high-quality, relevant, and timely data is greater than ever. Promising solutions lie in the collection and analysis of real-world data (RWD), which can potentially provide timely insights about the patient's course during and after initial treatment and the outcomes of important subgroups such as the elderly, rural populations, children, and patients with greater social health needs. However, to inform practice and policy, real-world evidence must be created from trustworthy and comprehensive sources of RWD; these may include pragmatic clinical trials, registries, prospective observational studies, electronic health records (EHRs), administrative claims, and digital technologies. There are unique challenges in oncology since key parameters (eg, cancer stage, biomarker status, genomic assays, imaging response, side effects, quality of life) are not recorded, siloed in inaccessible documents, or available only as free text or unstructured reports in the EHR. Advances in analytics, such as artificial intelligence, may greatly enhance the ability to obtain more granular information from EHRs and support integrated diagnostics; however, they will need to be validated purpose by purpose. We recommend a commitment to standardizing data across sources and building infrastructures that can produce fit-for-purpose RWD that will provide timely understanding of the effectiveness of individual interventions.

The sequelae of hematopoietic stem cell transplantation in adolescents and young adults: protocol for a systematic review.

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is a life-saving treatment for adolescents and young adults (ages 15-39) with hematologic malignancy. Given the significant developmental milestones usually achieved during this unique life stage, this population is especially vulnerable to the interruption caused by a cancer diagnosis and its treatment. HSCT is a particularly invasive form of cancer therapy with many negative physical, social, and psychological sequelae. The long-term impact of HSCT in adolescents and young adults with hematologic malignancies warrants a systematic investigation of its effects to best shape clinical care and health policy. METHODS: This protocol for a systematic review will focus on the long-term physical, psychological, social, spiritual, and health behavior effects experienced by adolescents and young adults who undergo HSCT for hematologic malignancy. We have constructed a specific search strategy that queries these five domains, which will be applied to five databases-Embase, PubMed, Cochrane Trials and Reviews, PsychInfo, and CINAHL-to identify the key literature. Two independent reviewers will perform a title/abstract screen followed by a full-text screen using standard screening templates to ensure the inclusion of outcomes in the post-acute HSCT period. Risk of bias will be assessed using the University of Adelaide Joanna Briggs Institute Collaboration Critical Appraisal Tools. Data from included studies will be abstracted on study characteristics, study setting, sample characteristics, and outcomes. Given the broad scope of the research question, data synthesis will focus on qualitative methods in accordance with Institute of Medicine standards. DISCUSSION: While adolescents and young adults undergoing hematopoietic stem cell transplantation for hematologic malignancy are understood to have a unique survivorship experience, the sequelae of this treatment approach in this population have not been previously aggregated. This systematic review intends to expand insight into the adolescent and young adult experiences with HSCT in order to inform age-appropriate survivorship care and deliver this life-saving intervention with the best possible outcomes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42022361663.

Moderators of Intervention Efficacy in the Pathways to Wellness Trial of Survivorship Education and Mindfulness Meditation for Younger Breast Cancer Survivors.

PURPOSE: Depression is associated with poor outcomes in breast cancer survivors (BCSs), with higher prevalence among younger women. The Pathways to Wellness (PTW; ClinicalTrials.gov identifier: NCT03025139) randomized controlled trial (RCT) demonstrated beneficial effects of two behavioral interventions (survivorship education [SE] and mindful awareness practices [MAPs]) on depressive symptoms in younger BCS. We conducted an exploratory secondary analysis to identify moderators of intervention effects. METHODS: Women diagnosed with stage 0 to III breast cancer at or before age 50 years who completed cancer treatment were randomly assigned to 6 weeks of SE (n = 81), MAPs (n = 85), or waitlist control (WLC; n = 81). Moderators assessed at baseline included psychological distress (depression and anxiety), intervention preference, preparedness for survivorship, and time since initial diagnosis. Linear regression models tested the modifying effects of each variable on postintervention depression in SE versus WLC and MAPs versus WLC. RESULTS: Baseline levels of depression (ß = -.03, P < .01) and anxiety (ß = -.64, P = .02) moderated effects of SE on depressive symptoms, as did preparedness for survivorship (ß = 3.17, P = .02). Participants randomly assigned to SE who had the highest levels of depression or anxiety and who felt least prepared for survivorship showed the largest reductions in depressive symptoms from preintervention to postintervention. Similar effects were not observed for MAPs. Intervention preference and time since diagnosis did not moderate intervention effects for either SE or MAPs. CONCLUSION: Our 6-week, group-based SE program may be most beneficial for women with higher levels of psychological distress and those who feel least prepared for cancer survivorship. By contrast, a 6-week mindfulness awareness practice intervention appears to benefit younger BCS regardless of pretreatment characteristics.

Development of a Web-Based Interactive Tool for Visualizing Breast Cancer Clinical Trial Tolerability Data.

PURPOSE: Longitudinal patient tolerability data collected as part of randomized controlled trials are often summarized in a way that loses information and does not capture the treatment experience. To address this, we developed an interactive web application to empower clinicians and researchers to explore and visualize patient tolerability data. METHODS: We used adverse event (AE) data (Common Terminology Criteria for Adverse Events) and patient-reported outcomes (PROs) from the NSABP-B35 phase III clinical trial, which compared anastrozole with tamoxifen for breast cancer-free survival, to demonstrate the tools. An interactive web application was developed using R and the Shiny web application framework that generates Sankey diagrams to visualize AEs and PROs using four tools: AE Explorer, PRO Explorer, Cohort Explorer, and Custom Explorer. RESULTS: To illustrate how users can use the interactive tool, examples for each of the four applications are presented using data from the NSABP-B35 phase III trial and the NSABP-B30 trial for the Custom Explorer. In the AE and PRO explorers, users can select AEs or PROs to visualize within specified time periods and compare across treatments. In the cohort explorer, users can select a subset of patients with a specific symptom, severity, and treatment received to visualize the trajectory over time within a specified time interval. With the custom explorer, users can upload and visualize structured longitudinal toxicity and tolerability data. CONCLUSION: We have created an interactive web application and tool for clinicians and researchers to explore and visualize clinical trial tolerability data. This adaptable tool can be extended for other clinical trial data visualization and incorporated into future patient-clinician interactions regarding treatment decisions.

Financial hardship and neighborhood socioeconomic disadvantage in long-term childhood cancer survivors.

BACKGROUND: Long-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships. METHODS: We performed a cross-sectional analysis of data from the Childhood Cancer Survivor Study between 1970 and 1999 and self-reported financial information from 2017 to 2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material and financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear models estimated effect sizes between ADI and financial hardship adjusting for clinical factors and personal socioeconomic status. RESULTS: Analysis was restricted to 3475 long-term childhood cancer survivors and 923 sibling controls. Median ages at time of evaluation was 39 years (interquartile range [IQR] = 33-46 years and 47 years (IQR = 39-59 years), respectively. Survivors resided in areas with greater deprivation (ADI ≥ 50: 38.7% survivors vs 31.8% siblings; P < .001). One quintile increases in deprivation were associated with small increases in behavioral (second quintile, P = .017) and psychological financial hardship (second quintile, P = .009; third quintile, P = .014). Lower psychological financial hardship was associated with individual factors including greater household income (≥$60 000 income, P < .001) and being single (P = .048). CONCLUSIONS: Childhood cancer survivors were more likely to live in areas with socioeconomic deprivation. Neighborhood-level disadvantage and personal socioeconomic circumstances should be evaluated when trying to assist childhood cancer survivors with financial hardships.

Management of Fatigue in Adult Survivors of Cancer: ASCO-Society for Integrative Oncology Guideline Update.

PURPOSE: To update the ASCO guideline on the management of cancer-related fatigue (CRF) in adult survivors of cancer. METHODS: A multidisciplinary panel of medical oncology, geriatric oncology, internal medicine, psychology, psychiatry, exercise oncology, integrative medicine, behavioral oncology, nursing, and advocacy experts was convened. Guideline development involved a systematic literature review of randomized controlled trials (RCTs) published in 2013-2023. RESULTS: The evidence base consisted of 113 RCTs. Exercise, cognitive behavioral therapy (CBT), and mindfulness-based programs led to improvements in CRF both during and after the completion of cancer treatment. Tai chi, qigong, and American ginseng showed benefits during treatment, whereas yoga, acupressure, and moxibustion helped to manage CRF after completion of treatment. Use of other dietary supplements did not improve CRF during or after cancer treatment. In patients at the end of life, CBT and corticosteroids showed benefits. Certainty and quality of evidence were low to moderate for CRF management interventions. RECOMMENDATIONS: Clinicians should recommend exercise, CBT, mindfulness-based programs, and tai chi or qigong to reduce the severity of fatigue during cancer treatment. Psychoeducation and American ginseng may be recommended in adults undergoing cancer treatment. For survivors after completion of treatment, clinicians should recommend exercise, CBT, and mindfulness-based programs; in particular, CBT and mindfulness-based programs have shown efficacy for managing moderate to severe fatigue after treatment. Yoga, acupressure, and moxibustion may also be recommended. Patients at the end of life may be offered CBT and corticosteroids. Clinicians should not recommend L-carnitine, antidepressants, wakefulness agents, or routinely recommend psychostimulants to manage symptoms of CRF. There is insufficient evidence to make recommendations for or against other psychosocial, integrative, or pharmacological interventions for the management of fatigue.Additional information is available at www.asco.org/survivorship-guidelines.

Phase III Randomized, Placebo-Controlled Trial of Endocrine Therapy ± 1 Year of Everolimus in Patients With High-Risk, Hormone Receptor-Positive, Early-Stage Breast Cancer.

PURPOSE: Phosphatidylinositol 3-kinase/AKT-serine threonine kinase/mammalian target of rapamycin (mTOR) pathway abnormalities contribute to endocrine resistance. Everolimus, an mTOR inhibitor, improved progression-free survival in hormone receptor-positive metastatic breast cancer (BC) when combined with endocrine therapy (ET). In this phase III randomized, placebo-controlled trial, we assessed the efficacy of everolimus + ET as adjuvant therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC after adjuvant/neoadjuvant chemotherapy. METHODS: Patients were randomly assigned 1:1 to physician's choice ET and 1 year of everolimus (10 mg orally once daily) or placebo stratified by risk group. The primary end point was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test with the hazard ratio (HR) estimated by Cox regression. Subset analyses included preplanned evaluation by risk group and exploratory analyses by menopausal status and age. Secondary end points included overall survival (OS) and safety. Everolimus did not improve IDFS/OS when added to ET in patients with early-stage high-risk, hormone receptor-positive BC. RESULTS: One thousand and nine hundred thirty-nine patients were randomly assigned with 1,792 eligible for analysis. Overall, no benefit of everolimus was seen for IDFS (HR, 0.94 [95% CI, 0.77 to 1.14]) or OS (HR, 0.97 [95% CI, 0.75 to 1.26]). The assumption of proportional hazards was not met suggesting significant variability in the HR over time since the start of treatment. In an unplanned subgroup analysis among postmenopausal patients (N = 1,221), no difference in IDFS (HR, 1.08 [95% CI, 0.86 to 1.36]) or OS (HR, 1.19 [95% CI, 0.89 to 1.60]) was seen. In premenopausal patients (N = 571), everolimus improved both IDFS (HR, 0.64 [95% CI, 0.44 to 0.94]) and OS (HR, 0.49 [95% CI, 0.28 to 0.86]). Treatment completion rates were lower in the everolimus arm compared with placebo (48% v 73%) with higher grade 3 and 4 adverse events (35% v 7%). CONCLUSION: One year of adjuvant everolimus + ET did not improve overall outcomes. Subset analysis suggests mTOR inhibition as a possible target for patients who remain premenopausal after chemotherapy.

Patient-Reported Outcomes in OlympiA: A Phase III, Randomized, Placebo-Controlled Trial of Adjuvant Olaparib in gBRCA1/2 Mutations and High-Risk Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer.

PURPOSE: The OlympiA randomized phase III trial compared 1 year of olaparib (OL) or placebo (PL) as adjuvant therapy in patients with germline BRCA1/2, high-risk human epidermal growth factor receptor 2-negative early breast cancer after completing (neo)adjuvant chemotherapy ([N]ACT), surgery, and radiotherapy. The patient-reported outcome primary hypothesis was that OL-treated patients may experience greater fatigue during treatment. METHODS: Data were collected before random assignment, and at 6, 12, 18, and 24 months. The primary end point was fatigue, measured with the Functional Assessment of Chronic Illness Therapy-Fatigue scale. Secondary end points, assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire, Core 30 item, included nausea and vomiting (NV), diarrhea, and multiple functional domains. Scores were compared between treatment groups using mixed model for repeated measures. Two-sided P values <.05 were statistically significant for the primary end point. All secondary end points were descriptive. RESULTS: One thousand five hundred and thirty-eight patients (NACT: 746, ACT: 792) contributed to the analysis. Fatigue severity was statistically significantly greater for OL versus PL, but not clinically meaningfully different by prespecified criteria (≥3 points) at 6 months (diff OL v PL: NACT: -1.3 [95% CI, -2.4 to -0.2]; P = .022; ACT: -1.3 [95% CI, -2.3 to -0.2]; P = .017) and 12 months (NACT: -1.6 [95% CI, -2.8 to -0.3]; P = .017; ACT: -1.3 [95% CI, -2.4 to -0.2]; P = .025). There were no significant differences in fatigue severity between treatment groups at 18 and 24 months. NV severity was worse in patients treated with OL compared with PL at 6 months (NACT: 6.0 [95% CI, 4.1 to 8.0]; ACT: 5.3 [95% CI, 3.4 to 7.2]) and 12 months (NACT: 6.4 [95% CI, 4.4 to 8.3]; ACT: 4.5 [95% CI, 2.8 to 6.1]). During treatment, there were some clinically meaningful differences between groups for other symptoms but not for function subscales or global health status. CONCLUSION: Treatment-emergent symptoms from OL were limited, generally resolving after treatment ended. OL- and PL-treated patients had similar functional scores, slowly improving during the 24 months after (N)ACT and there was no clinically meaningful persistence of fatigue severity in OL-treated patients.