Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): patient-reported outcomes from a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: In DESTINY-Breast02, patients with HER2-positive unresectable or metastatic breast cancer who received trastuzumab deruxtecan demonstrated superior progression-free and overall survival compared with those receiving treatment of physician's choice. We present the patient-reported outcomes (PROs) and hospitalisation data. METHODS: In this randomised, open-label, phase 3 trial conducted at 227 clinical sites globally, enrolled patients had to be aged 18 years or older with HER2-positive unresectable or metastatic breast cancer that had progressed on trastuzumab emtansine and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (2:1) using block randomisation (block size of 3) to receive trastuzumab deruxtecan (5·4 mg/kg intravenously once every 21 days) or treatment of physician's choice by an independent biostatistician using an interactive web-based system. Patients and investigators remained unmasked to treatment. Treatment of physician's choice was either capecitabine (1250 mg/m2 orally twice per day on days 1-14) plus trastuzumab (8 mg/kg intravenously on day 1 then 6 mg/kg once per day) or capecitabine (1000 mg/m2) plus lapatinib (1250 mg orally once per day on days 1-21), with a 21-day schedule. The primary endpoint, which was progression-free survival based on blinded independent central review, has previously been reported. PROs were assessed in the full analysis set (all patients randomly assigned to the study) using the oncology-specific European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), breast cancer-specific EORTC Quality of Life Questionnaire Breast 45 (QLQ-BR45), and the generic HRQoL EQ-5D-5L questionnaire. Analyses included change from baseline and time to definitive deterioration for PRO variables of interest and hospitalisation-related endpoints. This study is registered with ClinicalTrials.gov, NCT03523585, and is closed to recruitment. FINDINGS: Between Sept 6, 2018, and Dec 31, 2020, 608 patients were randomly assigned to receive either trastuzumab deruxtecan (n=406; two did not receive treatment) or treatment of physician's choice (n=202; seven did not receive treatment). Overall, 603 patients (99%) were female and five (<1%) were male. The median follow-up was 21·5 months (IQR 15·2-28·4) in the trastuzumab deruxtecan group and 18·6 months (IQR 8·8-26·0) in the treatment of physician's choice group. Median treatment duration was 11·3 months (IQR 6·2-20·5) in the trastuzumab deruxtecan group and approximately 4·5 months in the treatment of physician's choice group (4·4 months [IQR 2·5-8·7] with trastuzumab; 4·6 months [2·1-8·9] with capecitabine; and 4·5 months [2·1-10·6] with lapatinib). Baseline EORTC QLQ-C30 global health status (GHS) scores were similar with trastuzumab deruxtecan (n=393) and treatment of physician's choice (n=187), and remained stable with no clinically meaningful change (defined as ≥10-point change from baseline) over time. Median time to definitive deterioration was delayed with trastuzumab deruxtecan compared with treatment of physician's choice for the primary PRO variable EORTC QLQ-C30 GHS (14·1 months [95% CI 10·4-18·7] vs 5·9 months [4·3-7·9]; HR 0·5573 [0·4376-0·7099], p<0·0001) and all other prespecified PROs (EORTC QLQ-C30 subscales, EORTC QLQ-BR45 arm and breast symptoms, and EQ-5D-5L visual analogue scale). Patient hospitalisation rates were similar in the trastuzumab deruxtecan (92 [23%] of 406) and treatment of physician's choice (41 [20%] of 202) groups; however, median time to hospitalisation was 133 days (IQR 56-237) with trastuzumab deruxtecan versus 83 days (30-152) with treatment of physician's choice. INTERPRETATION: Overall, GHS and quality of life were maintained for both treatment groups, with prespecified PRO variables favouring trastuzumab deruxtecan over treatment of physician's choice, suggesting that despite a longer treatment duration, there was no detrimental impact on patient health-related quality of life with trastuzumab deruxtecan. When considered with efficacy and safety data from DESTINY-Breast02, these results support the overall benefit of trastuzumab deruxtecan for patients with HER2-positive unresectable or metastatic breast cancer previously treated with trastuzumab emtansine. FUNDING: Daiichi Sankyo and AstraZeneca.

Patient-reported symptom monitoring and adherence to therapy in patients with newly diagnosed chronic myeloid leukemia.

BACKGROUND: The authors assessed the clinical utility of patient-reported symptom monitoring in the setting of newly diagnosed chronic myeloid leukemia (CML). The primary objective was to evaluate adherence to therapy. METHODS: The authors conducted an international prospective study that included patients with newly diagnosed, chronic-phase CML. Before clinical consultation, patients were provided a tablet computer to self-rate their symptoms, and the results were available in real time to each physician during the patient's visit. Adherence was assessed by pill count and with a validated self-reported questionnaire. The proportions of optimal responders at 3 and 6 months were assessed according to the European LeukemiaNet criteria. RESULTS: Between July 2020 and August 2021, 94 patients with a median age of 57 years were enrolled. Pill count adherence analysis indicated that 86 of 93 evaluable patients (92.5%) took at least 90% of prescribed tyrosine kinase inhibitor therapy during the 6-month observation period. The online platform was well accepted by patients and physicians. An optimal response was achieved by 69 of 79 patients (87.3%) at 3 months and by 61 of 81 patients (75.3%) at 6 months. CONCLUSIONS: Patient-reported symptom monitoring from the beginning of therapy in patients with CML may be critical to improve adherence to therapy and early molecular response rates (ClinicalTrials.gov identifier NCT04384848).

Real-Time AI-Assisted Push-Broom Hyperspectral System for Precision Agriculture.

In the ever-evolving landscape of modern agriculture, the integration of advanced technologies has become indispensable for optimizing crop management and ensuring sustainable food production. This paper presents the development and implementation of a real-time AI-assisted push-broom hyperspectral system for plant identification. The push-broom hyperspectral technique, coupled with artificial intelligence, offers unprecedented detail and accuracy in crop monitoring. This paper details the design and construction of the spectrometer, including optical assembly and system integration. The real-time acquisition and classification system, utilizing an embedded computing solution, is also described. The calibration and resolution analysis demonstrates the accuracy of the system in capturing spectral data. As a test, the system was applied to the classification of plant leaves. The AI algorithm based on neural networks allows for the continuous analysis of hyperspectral data relative up to 720 ground positions at 50 fps.

The prognostic value of patient-reported outcomes in allogeneic hematopoietic stem cell transplantation: exploratory analysis of a randomized nutrition intervention trial.

Whether patient-reported outcomes (PROs) can predict overall survival (OS) and non-relapse mortality (NRM) among recipients of allogeneic stem cell transplantation (allo-HSCT), is unclear. We performed an exploratory analysis of the prognostic value of patient-reported outcomes (PROs) among 117 recipients of allogeneic stem cell transplantation (allo-HSCT) who participated in a randomized nutrition intervention trial. Cox proportional hazards models were used to investigate possible associations between PROs collected pre-allo-HSCT (baseline) using scores from the EORTC Quality of Life Questionnaire-Core 30 (QLQ-C30) and 1-year overall survival (OS), whereas logistic regression was used to study associations between these PROs and 1-year non-relapse mortality (NRM). Multivariable analyses indicated that only the Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) and the European Bone Marrow Transplantation (EBMT) risk score were associated with 1-year OS. In the multivariable model including clinical-sociodemographic factors for 1-year NRM, our analysis showed that living alone (p=0.009), HCT-CI (p=0.016), EBMT risk score (p=0.002), and stem cell source (p=0.046) could be associated with 1-year NRM. Moreover, in the multivariable model, our analysis showed that only appetite loss from the QLQ-C30 was associated with 1-year NRM (p=0.026). In conclusion, in this specific setting, our analysis suggests that the commonly used HCT-CI and EBMT risk scores could be predictive for both 1-year OS and 1-year NRM, whereas baseline PROs in general were not.

Health-related quality of life profile of patients with immune thrombocytopenia in the real life is impaired by splenectomy.

The impact of splenectomy on health-related quality of life (HRQoL) in patients with immune thrombocytopenia (ITP) remains scarcely explored. Therefore, we evaluated HRQoL with the 36-Item Short-Form Health Survey (SF-36) in an internal cohort of 69 chronic ITP patients, overall and by type of treatment. Of these patients, 26 patients were splenectomized, while other patients were treated medically with thrombopoietin-receptor agonists (TPO-RAs) or immunosuppressive treatment. We also compared HRQoL of the splenectomized patients (internal cohort) with an external cohort of 63 splenectomized ITP patients and the general population. The median follow-up was 10 years (range 1-20). Splenectomized patients had a worse overall HRQoL profile than those who received medical therapy either with TPO-RAs or other treatments (OT), with clinically meaningful differences registered in several domains. These included physical functioning (Δ = - 17.0 and Δ = - 15.2, for TPO-Ras and OT, respectively, p = 0.065), role physical (Δ = - 9.7 and Δ = - 13.8, p = 0.483), and bodily pain (Δ = - 14.2 and Δ = - 18.8, p = 0.053). Compared to the general population, both internal and external splenectomized cohorts had an impaired HRQoL profile. Further studies on HRQoL in splenectomized ITP patients are needed to better understand the long-term impact of this surgical procedure.

Investigating Trends in the Quality of Reporting of Patient-Reported Outcomes in Oncology Over Time: Analysis of 631 Randomized Controlled Trials Published Between 2004 and 2019.

OBJECTIVES: Incomplete reporting of key information on patient-reported outcomes (PROs) in randomized controlled trials (RCTs) in oncology has been highlighted repeatedly as a major barrier to the use of study findings in clinical practice. We investigated whether the quality of reporting of PRO data in cancer RCTs has improved over the last 15 years. METHODS: We identified all cancer RCTs with PRO endpoints conducted across the most prevalent solid tumor types worldwide published between 2004 and 2019. The quality of PRO reporting was assessed using the International Society for Quality of Life Research recommended standards, which include important aspects related to assessment methodology, statistical analyses, and interpretation of data. RESULTS: We assessed a total of 631 cancer RCTs in breast (n = 187), lung (n = 131), prostate (n = 120), colorectal (n = 107), and gynecological (n = 86) cancer. We observed a higher adherence to the International Society for Quality of Life Research reporting criteria in the more recently published studies. In a multivariable linear regression analysis, we observed a statistically significant improvement in the quality of PRO reporting over time (P<.001), and this relationship was independent of other measured confounding factors, such as sample size and study sponsorship. Overall, the quality of PRO reporting was higher for studies published after the publication of the Consolidated Standards of Reporting Trials-PRO Extension. CONCLUSIONS: The quality of PRO reporting in cancer RCTs published in the last 15 years has improved significantly. Our findings are encouraging because better reporting of PRO results may translate into a greater impact of study findings on real-world practice.

Past and Current Practice of Patient-Reported Outcome Measurement in Randomized Cancer Clinical Trials: A Systematic Review.

OBJECTIVES: In our systematic review, we assessed past and current practice of patient-reported outcome (PRO) measurement in cancer randomized, controlled trials (RCTs). METHODS: We included RCTs with PRO endpoints evaluating conventional medical treatments, conducted in patients with the most prevalent solid tumor types (breast, lung, colorectal, prostate, bladder, and gynecological cancers) and either published in 2004 to 2018 or registered on clinicaltrials.gov and initiated in 2014 to 2019. Frequency of use of individual PRO measures was assessed overall, over time, and by cancer site. RESULTS: Screening of 42 095 database records and 3425 registered trials identified 480 published and 537 registered trials meeting inclusion criteria. Among published trials, the European Organisation for Research and Treatment of Cancer (EORTC) measures were used most often (54.8% of trials), followed by the Functional Assessment of Chronic Illness Therapy (FACIT) measures (35.8%), the EQ-5D (10.2%), the SF-36 (7.3%), and the MD Anderson Symptom Inventory (MDASI; 2.5%). Among registered trials, the EORTC measures were used in 66.1% of the trials, followed by the FACIT measures (25.9%), the EQ-5D (23.1%), the SF-36 (4.8%), the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE; 2.2%), the Patient-Reported Outcomes Measurement Information System (PROMIS) measures (1.7%), and the MDASI measures (1.1%). CONCLUSION: The PRO measures most frequently used in RCTs identified in our review differ substantially in terms of content and domains, reflecting the ongoing debate among the scientific community, healthcare providers, and regulators on the type of PRO to be measured. Current findings may contribute to better informing the development of an internationally agreed core outcome set for future cancer trials.

Patient-Reported Outcomes as Independent Prognostic Factors for Survival in Oncology: Systematic Review and Meta-Analysis.

OBJECTIVES: Assessment of patient-reported outcomes (PROs) in oncology is of critical importance because it provides unique information that may also predict clinical outcomes. METHODS: We conducted a systematic review of prognostic factor studies to examine the prognostic value of PROs for survival in cancer. A systematic literature search was performed in PubMed for studies published between 2013 and 2018. We considered any study, regardless of the research design, that included at least 1 PRO domain in the final multivariable prognostic model. The protocol (EPIPHANY) was published and registered in the International Prospective Register of Systematic Reviews (CRD42018099160). RESULTS: Eligibility criteria selected 138 studies including 158 127 patients, of which 43 studies were randomized, controlled trials. Overall, 120 (87%) studies reported at least 1 PRO to be statistically significantly prognostic for overall survival. Lung (n = 41, 29.7%) and genitourinary (n = 27, 19.6%) cancers were most commonly investigated. The prognostic value of PROs was investigated in secondary data analyses in 101 (73.2%) studies. The EORTC QLQ-C30 questionnaire was the most frequently used measure, and its physical functioning scale (range 0-100) the most frequent independent prognostic PRO, with a pooled hazard ratio estimate of 0.88 per 10-point increase (95% CI 0.84-0.92). CONCLUSIONS: There is convincing evidence that PROs provide independent prognostic information for overall survival across cancer populations and disease stages. Further research is needed to translate current evidence-based data into prognostic tools to aid in clinical decision making.

Differences in Patient-Reported Outcomes That Are Most Frequently Detected in Randomized Controlled Trials in Patients With Solid Tumors: A Pooled Analysis of 229 Trials.

OBJECTIVES: Patient-reported outcome (PRO) measurements used in cancer research can assess a number of health domains. Our primary objective was to investigate which broad types of PRO domains (namely, functional health, symptoms, and global quality of life [QoL]) most frequently yielded significant differences between treatments in randomized controlled trials (RCTs). METHODS: A total of 229 RCTs published between January 2004 and February 2019, conducted on patients diagnosed with the most common solid malignancies and assessed using the European Organization for the Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-C30, were considered. Studies were identified systematically using literature searches in key electronic databases. Unlike other PRO measurements typically used in RCTs, the scoring algorithm of the multidimensional EORTC QLQ-C30 allowed us to clearly distinguish the 3 broad types of PRO domains. RESULTS: In total, 134 RCTs (58.5%) reported statistically significant differences between treatment arms for at least 1 of the QLQ-C30 domains. Most frequently, differences were reported for 2 or all 3 broad types of PRO domains (78 of 134 trials; 58.2%). In particular, 35 trials (26.1%) found significant differences for symptoms, functional health, and global QoL, 24 trials (17.9%) for symptoms and functional health, 11 trials (8.2%) for functional health and global QoL, and 8 trials (6.0%) for symptoms and global QoL. The likelihood of finding a statistically significant difference between treatment arms was not associated with key study characteristics, such as study design (ie, open-label vs blinded trials) and industry support. CONCLUSIONS: Our findings emphasize the importance of a multidimensional PRO assessment to most comprehensively capture the overall burden of therapy from the patients' standpoint.

Consistency matters: measurement invariance of the EORTC QLQ-C30 questionnaire in patients with hematologic malignancies.

PURPOSE: To ensure that observed differences in the scores of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) reflect actual differences in health-related quality of life (HRQoL) rather than measurement bias, measurement invariance needs to be established. We investigated the assumption of measurement invariance of the EORTC QLQ-C30 in patients with hematological malignancies across age, sex, comorbidity, disease type, and time. METHODS: We used a large database of patients with hematological malignancies, which included HRQoL data collected with the EORTC QLQ-C30. We used the structural equation modeling approach to test for measurement (metric and scalar) invariance across groups (age, sex, comorbidity, disease) and time (baseline, 1 month and 2 month follow-up). Longitudinal invariance was examined in a subgroup of patients diagnosed with myelodysplastic syndromes. RESULTS: Confirmatory factor analyses demonstrated full measurement invariance for age and comorbidity and over time, while support for partial scalar invariance was obtained for sex and disease. Violations of invariance for sex were observed for items of the physical functioning scale and the emotional functioning scale, while for disease type, violations of invariance were observed for items of the physical functioning scale, emotional functioning scale, and the cognitive functioning scale. CONCLUSIONS: Our findings support measurement invariance of the EORTC QLQ-C30 in a large sample of patients with hematological malignancies. The results showed that the number of non-invariant items was negligible, suggesting that this questionnaire is a valid and robust measurement tool in patients with hematological malignancies, also for comparisons across groups and time.

Validation of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 Summary Score in Patients With Hematologic Malignancies.

OBJECTIVES: We investigated the validity of the recently developed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) summary score in patients with hematologic malignancies. Specifically, we evaluated the adequacy of a single-factor measurement model for the QLQ-C30, and its known-groups validity and responsiveness to change over time. METHODS: We used confirmatory factor analysis to test the single-factor model of the QLQ-C30, using baseline QLQ-C30 data (N = 2134). The QLQ-C30 summary score was compared to the original QLQ-C30 scales using general (age, sex, Eastern Cooperative Oncology Group performance status, comorbidity) and disease-specific (red blood cell transfusion dependency) groups. Repeated measurements allowed us to investigate responsiveness to change in a subgroup of patients with acute myeloid leukemia. RESULTS: The single-factor model of the QLQ-C30 exhibited adequate fit in patients with hematologic malignancies. Known-group comparisons generally supported the construct validity of the summary score when using more general grouping variables (sociodemographics, broad clinical parameters). Nevertheless, when groups were formed on the basis of disease-specific variables (eg, transfusion dependency), the summary score performed less well the some of the original, separate scales of the QLQ-C30. CONCLUSION: Our findings provide support for the validity of the single-factor model of the EORTC QLQ-C30 in patients with hematologic malignancies. Specifically, the results suggest that the summary score can be used as an endpoint in this population when symptom- or other health domain-specific hypotheses are not available.

Propensity score methods and regression adjustment for analysis of nonrandomized studies with health-related quality of life outcomes.

PURPOSE: The aim of this study was to investigate the potential added value of combining propensity score (PS) methods with multivariable linear regression (MLR) in estimating the average treatment effect on the treated (ATT) in nonrandomized studies with health-related quality of life (HRQoL) outcomes. METHODS: We first used simulations to compare the performances of different PS-based methods, either alone or in combination with further MLR adjustment, in estimating ATT. PS methods were, respectively, optimal pair (OPM) and full (OFM) PS matching, subclassification on the PS (SBC), and the inverse probability of treatment weighting (IPTW). We simulated several scenarios, according to different sample sizes, proportions of treated vs untreated subjects, and types of HRQoL outcomes. We also applied the same methods to a real clinical data set. RESULTS: OPM and IPTW provided the closest Type I error to the nominal threshold α = 0.05 across all scenarios. Overall, both methods showed also lower variability in estimates than SBC and OFM. SBC performed worst, generally providing the highest levels of bias. Further MLR adjustment lessened bias for all methods, however providing higher Type I error for SBC and OFM. In the real case, all methods provided similar ATT estimates except for one outcome. CONCLUSIONS: Our findings suggest that for sample sizes up to n = 200, OPM and IPTW are to be preferred to OFM and SBC in estimating ATT on HRQoL outcomes. Specifically, OPM performed best in sample sizes of n ≥ 80, IPTW for smaller sample sizes. Additional MLR adjustment can further improve ATT estimates.

Modeling strategies to improve parameter estimates in prognostic factors analyses with patient-reported outcomes in oncology.

PURPOSE: The inclusion of patient-reported outcome (PRO) questionnaires in prognostic factor analyses in oncology has substantially increased in recent years. We performed a simulation study to compare the performances of four different modeling strategies in estimating the prognostic impact of multiple collinear scales from PRO questionnaires. METHODS: We generated multiple scenarios describing survival data with different sample sizes, event rates and degrees of multicollinearity among five PRO scales. We used the Cox proportional hazards (PH) model to estimate the hazard ratios (HR) using automatic selection procedures, which were based on either the likelihood ratio-test (Cox-PV) or the Akaike Information Criterion (Cox-AIC). We also used Cox PH models which included all variables and were either penalized using the Ridge regression (Cox-R) or were estimated as usual (Cox-Full). For each scenario, we simulated 1000 independent datasets and compared the average outcomes of all methods. RESULTS: The Cox-R showed similar or better performances with respect to the other methods, particularly in scenarios with medium-high multicollinearity (ρ = 0.4 to ρ = 0.8) and small sample sizes (n = 100). Overall, the Cox-PV and Cox-AIC performed worse, for example they did not select one or more prognostic collinear PRO scales in some scenarios. Compared with the Cox-Full, the Cox-R provided HR estimates with similar bias patterns but smaller root-mean-squared errors, particularly in higher multicollinearity scenarios. CONCLUSIONS: Our findings suggest that the Cox-R is the best approach when performing prognostic factor analyses with multiple and collinear PRO scales, particularly in situations of high multicollinearity, small sample sizes and low event rates.

Patient-reported outcomes in randomised clinical trials of bladder cancer: an updated systematic review.

BACKGROUND: Despite international recommendations of including patient-reported outcomes (PROs) in randomised clinical trials (RCTs), a 2014 review concluded that few RCTs of bladder cancer (BC) report PRO as an outcome. We therefore aimed to update the 2014 review to synthesise current evidence-based knowledge of PROs from RCTs in BC. A secondary objective was to examine whether quality of PRO reporting has improved over time and to provide evidence-based recommendations for future studies in this area. METHODS: We conducted a systematic literature search using PubMed/Medline, from April 2014 until June 2018. We included the RCTs identified in the previous review as well as newly published RCTs. Studies were evaluated using a predefined electronic-data extraction form that included information on basic trial demographics, clinical and PRO characteristics and standards of PRO reporting based on recommendation from the International Society of Quality of Life Research. RESULTS: Since April 2014 only eight new RCTs for BC included PROs as a secondary outcome. In terms of methodology, only the proportion of RCTs documenting the extent of missing PRO data (75% vs 11.1%, p = 0.03) and the identification of PROs in trial protocols (50% vs 0%, p = 0.015) improved. Statistical approaches for dealing with missing data were not reported in most new studies (75%). CONCLUSION: Little improvement into the uptake and assessment of PRO as an outcome in RCTs for BC has been made during recent years. Given the increase in (immunotherapy) drug trials with a potential for severe adverse events, there is urgent need to adopt the recommendations and standards available for PRO use in bladder cancer RCTs.

Health-related quality of life in patients with chronic myeloid leukemia receiving first-line therapy with nilotinib.

BACKGROUND: Although a wealth of efficacy and safety data is available for many tyrosine kinase inhibitors used in chronic myeloid leukemia (CML), there is a dearth of information on their impact on patients' health-related quality of life (HRQOL). The primary objective of this study was to evaluate HRQOL and fatigue outcomes in patients with CML receiving first-line therapy with nilotinib. METHODS: This was a multicenter, prospective study enrolling 130 patients with chronic-phase CML. HRQOL and fatigue were evaluated with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) and its validated Fatigue module at the baseline and then at 3, 6, 12, 18, and 24 months. The primary prespecified HRQOL endpoints defined in the study protocol for longitudinal analysis were the Physical Functioning, Social Functioning, Role Functioning, and Fatigue scales. The remaining scales were investigated on an exploratory basis. RESULTS: The rate of baseline compliance with the HRQOL assessment was 95.4% (124 of 130), and the rate of overall compliance with HRQOL forms was 91%. Among the 4 prespecified primary HRQOL endpoints, statistically significant improvements over time were found for Physical Functioning (P = .013), Role Functioning (P = .004), and Fatigue (P < .001). Clinically meaningful improvements were found already 3 months after the treatment start. The baseline patient self-reported fatigue severity was an independent predictive factor for the achievement of a major molecular response with an odds ratio of 0.960 (95% confidence interval, 0.934-0.988; P = .005). CONCLUSIONS: For most patients, HRQOL improvements with nilotinib occur during the early phase of therapy and are maintained over time. Also, a more systematic HRQOL evaluation during the diagnostic workup of CML may help to predict clinical outcomes. Cancer 2018;124:2228-37. © 2018 American Cancer Society.

Patient-reported outcomes enhance the survival prediction of traditional disease risk classifications: An international study in patients with myelodysplastic syndromes.

BACKGROUND: Current prognostic systems for myelodysplastic syndromes (MDS) are based on clinical, pathologic, and laboratory indicators. The objective of the current study was to develop a new patient-centered prognostic index for patients with advanced MDS by including self-reported fatigue severity into a well-established clinical risk classification: the International Prognostic Scoring System (IPSS). METHODS: A total of 469 patients with advanced (ie, IPSS intermediate-2 or high-risk) MDS were analyzed. Untreated patients (280 patients) were recruited into an international prospective cohort observational study to create the index. The index then was applied to an independent cohort including pretreated patients with MDS from the Dana-Farber Cancer Institute in Boston, Massachusetts (189 patients). At baseline, patients completed the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). RESULTS: A new prognostic index was developed: the FA-IPSS(h), in which FA stands for fatigue and h for higher-risk. This new risk classification enabled the authors to distinguish 3 subgroups of patients with distinct survival outcomes (ie, risk-1, risk-2, and risk-3). Patients classified as FA-IPSS(h) risk-1 had a median overall survival (OS) of 23 months (95% confidence interval [95% CI], 19-29 months), whereas those with risk-2 had a median OS of 16 months (95% CI, 12-17 months) and those with risk-3 had a median OS of 10 months (95% CI, 4-13 months). The predictive accuracy of this new index was higher than that of the IPSS alone in both the development cohort as well as in the independent cohort including pretreated patients. CONCLUSIONS: The FA-IPSS(h) is a novel patient-centered prognostic index that includes patients' self-reported fatigue severity. The authors believe its use might enhance physicians' ability to predict survival more accurately in patients with advanced MDS. Cancer 2018;124:1251-9. © 2017 American Cancer Society.

Distribution- and anchor-based methods to determine the minimally important difference on patient-reported outcome questionnaires in oncology: a structured review.

BACKGROUND: Interpretation of differences or changes in patient-reported outcome scores should not only consider statistical significance, but also clinical relevance. Accordingly, accurate determination of the minimally important difference (MID) is crucial to assess the effectiveness of health care interventions, as well as for sample size calculation. Several methods have been proposed to determine the MID. Our aim was to review the statistical methods used to determine MID in patient-reported outcome (PRO) questionnaires in cancer patients, focusing on the distribution- and anchor-based approaches and to present the variability of criteria used as well as possible limitations. METHODS: We performed a systematic search using PubMed. We searched for all cancer studies related to MID determination on a PRO questionnaire. Two reviewers independently screened titles and abstracts to identify relevant articles. Data were extracted from eligible articles using a predefined data collection form. Discrepancies were resolved by discussion and the involvement of a third reviewer. RESULTS: Sixty-three articles were identified, of which 46 were retained for final analysis. Both distribution- and anchor-based approaches were used to assess the MID in 37 studies (80.4%). Different time points were used to apply the distribution-based method and the most frequently reported distribution was the 0.5 standard deviation at baseline. A change in a PRO external scale (N = 13, 30.2%) and performance status (N = 15, 34.9%) were the most frequently used anchors. The stability of the MID over time was rarely investigated and only 28.2% of studies used at least 3 assessment timepoints. The robustness of anchor-based MID was questionable in 37.2% of the studies where the minimal number of patients by anchor category was less than 20. CONCLUSION: Efforts are needed to improve the quality of the methodology used for MID determination in PRO questionnaires used in oncology. In particular, increased attention to the sample size should be paid to guarantee reliable results. This could increase the use of these specific thresholds in future studies.

A prospective observational study to assess clinical decision-making, prognosis, quality of life and satisfaction with care in patients with relapsed/refractory multiple myeloma: the CLARITY study protocol.

BACKGROUND: Treatment decision-making in patients with relapsed/refractory multiple myeloma (RRMM) is challenging for a number of reasons including, the heterogeneity of disease at relapse and the number of possible therapeutic approaches. This study broadly aims to generate new evidence-based data to facilitate clinical decision-making in RRMM patients. The primary objective is to investigate the prognostic value of patient self-reported fatigue severity for overall survival. METHODS: This multicenter prospective observational study will consecutively enroll 312 patients with multiple myeloma who have received at least 1 prior line of therapy and are considered as RRMM according to the International Myeloma Working Group (IMWG) criteria. Eligible RRMM participants will be adults (≥ 18 years old) patients and will be enrolled irrespective of comorbidities and performance status. At the time of study inclusion, data to calculate the frailty score are to be available. Patients will be followed up for 30 months and patient-reported outcome (PRO) assessment is planned at baseline and thereafter at 3, 6, 12, and 24 months. The following PRO validated questionnaires will be used: the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30), the EORTC QLQ-MY20 and the EORTC QLQ-INFO25. Satisfaction with care and preference for involvement in treatment decisions will also be evaluated. Clinical, laboratory and treatment related information will be prospectively collected in conjunction with pre scheduled PRO assessments. Cox regression analyses will be used to assess the prognostic value of baseline fatigue severity (EORTC QLQ-C30) and other patient-reported health-related quality of life parameters. DISCUSSION: Clinical decision-making in RRMM is a challenge and outcome prediction is also an important aspect to enhance personalized treatment planning. Given the paucity of PRO data in this population, this prospective observational study aims to provide novel information that may facilitate patients' management in routine practice. TRIAL REGISTRATION: This trial is registered as identifier NCT03190525 .

Physicians' attitude towards selection of second line therapy with nilotinib and dasatinib in chronic myeloid leukemia patients.

We investigated factors that physicians consider of most importance in the selection of second line tyrosine kinase inhibitors treatments (TKIs) in chronic myeloid leukemia patients (CML).

Health-related quality of life and burden of fatigue in patients with primary immune thrombocytopenia by phase of disease.

The main objective of this study was to compare health-related quality of life (HRQOL) of primary immune thrombocytopenia (pITP) patients with that of general population, overall, and by patient group (i.e., newly diagnosed, persistent, and chronic patients). Fatigue was also investigated as a secondary objective. Overall, 424 adult patients were enrolled in a multicenter observational study and the control group consisted of a representative sample from the general population. Propensity score matching plus further multivariate linear regression adjustment was used to compare HRQOL outcomes between pITP patients and general population. Mean age of patients was 54 years. Of those with HRQOL assessment, 99 patients (23.6%) were newly diagnosed, 53 (12.6%) were persistent, and 268 (63.8%) were chronic pITP patients. Comparison by patient group versus their respective peers in the general population revealed greater impairments in persistent pITP patients. Persistent pITP patients reported clinically meaningful impairments in physical functioning (-15; 95% CI -24.1 to -5.8; P = 0.002), social functioning (-15.3; 95% CI -25.5 to -5.1; P = 0.004), role physical (-28.4; 95% CI -43.1 to -13.7; P < 0.001), role emotional (-23.9; 95% CI -40.1 to -7.7; P = 0.004), and mental health scales (-11.3; 95% CI -21.2 to -1.4; P = 0.026) of the SF-36 questionnaire. Higher fatigue severity was associated with lower physical and mental HRQOL outcomes. Our findings suggest that the burden of the disease and treatment might depend on the disease phase and that persistent pITP patients are the most vulnerable subgroup. Am. J. Hematol. 91:995-1001, 2016. © 2016 Wiley Periodicals, Inc.