Patient-reported Outcome Measurement and Reporting for Patients with Advanced Renal Cell Carcinoma: A Systematic Literature Review.

CONTEXT: In the oncology setting, patient-reported outcome measures (PROMs) provide important data that help to ensure patient-relevant endpoints are captured and reported. Use of this information for treatment decision-making by clinicians and patients in real-world settings is facilitated by consistent and transparent reporting of trial methods. OBJECTIVE: To identify and compare PROMs used in advanced renal cell carcinoma (RCC) trials in terms of the rationale for the choice of measure, endpoint hierarchy (primary, secondary, exploratory), assessment time points, statistical methods, and statistical metrics for interpretation. EVIDENCE ACQUISITION: A systematic literature review via searches of four online databases (2016-2021) and recent conference abstracts (2019-2021) identified 2616 articles, of which 33 were included in the review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. EVIDENCE SYNTHESIS: Among the 33 clinical studies included, 19 different PROMs were identified: three kidney cancer-specific scales, two cancer-specific scales, two generic scales, and 12 symptom-specific scales. The endpoint hierarchy for patient reported outcome (PRO) assessment was reported in 42% of the studies; one study included PROs as a primary endpoint. Reporting of time points, minimal important differences, and statistical analyses was highly heterogeneous. CONCLUSIONS: A diverse range of PROMs have been included in clinical studies for patients with advanced/metastatic RCC. Prespecified analyses for PRO assessments were generally not stated, while analytical methods and reporting varied. An improvement in alignment across studies would better inform regulatory, market-access, reimbursement, and clinical decision-making to improve patient care. PATIENT SUMMARY: We reviewed how the impact of cancer therapies on health outcomes from the patient's point of view is being measured in clinical trials for kidney cancer. The techniques and reporting varied across trials. Standardisation of how these data are captured and reported may improve care and decision-making for patients with kidney cancer.

Health-related quality of life with pembrolizumab or placebo plus chemotherapy with or without bevacizumab for persistent, recurrent, or metastatic cervical cancer (KEYNOTE-826): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the KEYNOTE-826 study, the addition of the anti-PD-1 monoclonal antibody pembrolizumab to chemotherapy with or without bevacizumab improved overall survival and progression-free survival (primary endpoints) versus placebo plus chemotherapy with or without bevacizumab, with manageable toxicity, in patients with persistent, recurrent, or metastatic cervical cancer. In this Article, we report patient-reported outcomes (PROs) from KEYNOTE-826. METHODS: KEYNOTE-826 is a multicentre, randomised, phase 3 trial in 151 cancer treatment centres in 19 countries. Eligible patients were aged 18 years or older with persistent, recurrent, or metastatic cervical cancer not previously treated with systemic chemotherapy (previous radiosensitising chemotherapy was allowed) and not amenable to curative treatment and had an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) centrally by means of an interactive voice response system in a double-blind manner to receive either pembrolizumab 200 mg or placebo every 3 weeks intravenously for up to 35 cycles plus chemotherapy (paclitaxel 175 mg/m2 plus cisplatin 50 mg/m2 or carboplatin area under the curve 5 mg/mL per min, intravenously) with or without bevacizumab 15 mg/kg every 3 weeks intravenously. Randomisation (block size of 4) was stratified by metastatic disease at diagnosis, planned bevacizumab use, and PD-L1 combined positive score. Patients, investigators, and other study personnel involved in study treatment administration or clinical evaluation of patients were unaware of treatment group assignments. PRO instruments were the EORTC Quality-of-Life-Core 30 (QLQ-C30), the EORTC cervical cancer module (QLQ-CX24), and the EuroQol-5 dimension-5 level (EQ-5D-5L) visual analogue scale, each collected before treatment at cycles 1-14 and every other cycle thereafter. Primary endpoints were overall survival and progression-free survival per RECIST version 1.1 by investigator review. Change from baseline in QLQ-C30 global health status (GHS)-quality of life (QoL) was a prespecified secondary endpoint and was assessed in the PRO full analysis population (all patients who received at least one dose of study treatment and completed at least one post-baseline PRO assessment). Other PRO analyses were protocol-specified exploratory endpoints. The study is registered with ClinicalTrials.gov, NCT03635567, and is ongoing. FINDINGS: Between Nov 20, 2018, and Jan 31, 2020, of 883 patients screened, 617 were randomly assigned (pembrolizumab group, n=308; placebo group, n=309). 587 (95%) of 617 patients received at least one dose of study treatment and completed at least one post-baseline PRO assessment and were therefore included in the PRO analyses (pembrolizumab group, n=290; placebo group, n=297). Median follow-up was 22·0 months (IQR 19·1-24·4). At week 30, QLQ-C30 completion was 199 (69%) of 290 patients in the pembrolizumab group and 168 (57%) of 297 patients in the placebo group; compliance was 199 (94%) of 211 and 168 (90%) of 186, respectively. The least squares mean change in QLQ-C30 GHS-QoL score from baseline to week 30 was -0·3 points (95% CI -3·1 to 2·6) in the pembrolizumab group and -1·3 points (-4·2 to 1·7) in the placebo group, with a between-group difference in least squares mean change of 1·0 point (95% CI -2·7 to 4·7). Median time to true deterioration in GHS-QoL was not reached (NR; 95% CI 13·4 months-NR) in the pembrolizumab group and 12·9 months (6·6-NR) in the placebo group (hazard ratio 0·84 [95% CI 0·65-1·09]). 122 (42%) of 290 patients in the pembrolizumab group versus 85 (29%) of 297 in the placebo group had improved GHS-QoL at any time during the study (p=0·0003). INTERPRETATION: Addition of pembrolizumab to chemotherapy with or without bevacizumab did not negatively affect health-related quality of life. Along with the efficacy and safety results already reported from KEYNOTE-826, these data support the benefit of pembrolizumab and the value of immunotherapy in patients with recurrent, persistent, or metastatic cervical cancer. FUNDING: Merck Sharp & Dohme.

Improvements in Objective and Subjective Measures of Chronic Cough with Gefapixant: A Pooled Phase 3 Efficacy Analysis of Predefined Subgroups.

INTRODUCTION: In phase 3 trials (COUGH-1/COUGH-2), gefapixant 45 mg twice daily significantly reduced 24-h cough frequency vs placebo in refractory or unexplained chronic cough (RCC or UCC). METHODS: Here, the efficacy of gefapixant 45 mg vs placebo was evaluated across COUGH-1/COUGH-2 in predefined subgroups based on sex, region, age, cough duration, cough severity, cough frequency, and diagnosis (RCC, UCC). Awake cough frequency reductions at Week 12 and LCQ response rates (i.e., ≥ 1.3-point improvement) at Week 24 were assessed. RESULTS: Among 1360 participants analyzed, gefapixant 45 mg resulted in consistent awake cough frequency reductions overall and across predefined subgroups at Week 12. Gefapixant also resulted in improved LCQ scores across subgroups at Week 24; ≥ 70% of participants in each subgroup treated with gefapixant 45 mg had an LCQ response. CONCLUSION: These data suggest gefapixant 45 mg provides consistent objective and subjective efficacy across subgroups of individuals with RCC or UCC.

Validation of a visual analog scale for assessing cough severity in patients with chronic cough.

INTRODUCTION: Patients with chronic cough experience considerable burden. The cough severity visual analog scale (VAS) records patients' assessment of cough severity on a 100-mm linear scale ranging from "no cough" (0 mm) to "worst cough" (100 mm). Although cough severity scales are widely used in clinical practice and research, their use in patients with refractory or unexplained chronic cough has not been formally validated. METHODS: This analysis includes data from a phase 2b randomized controlled trial of the P2X3-receptor antagonist gefapixant for treatment of refractory or unexplained chronic cough (NCT02612610). Cough severity VAS scores were assessed at baseline and Weeks 4, 8, and 12. The cough severity VAS was validated using several outcomes, including the Cough Severity Diary (CSD), Leicester Cough Questionnaire (LCQ), patient global impression of change (PGIC) scale, and objective cough frequency. Validation metrics included test-retest reliability, convergent and known-groups validity, responsiveness, and score interpretation (i.e., clinically meaningful change threshold). RESULTS: The analysis included 253 patients (median age, 61.0 years; females, 76%). Test-retest reliability of the cough severity VAS was moderate (intraclass correlation coefficient, 0.51). The cough severity VAS had acceptable convergent validity with other related measures (Pearson r of 0.53 and -0.41 for CSD and LCQ total scores, respectively; p < 0.0001 for each). Known-groups validity was supported by significant differences in mean cough severity VAS scores across severity groups defined using CSD, LCQ, and cough frequency tertiles. A large effect size was observed in patients with the greatest improvements in PGIC (Cohen d = -1.8). A ⩾ 30-mm reduction in the cough severity VAS was estimated as a clinically meaningful change threshold for clinical trials in chronic cough. CONCLUSIONS: The cough severity VAS is a valid and responsive measure. A cough severity VAS reduction of ⩾ 30 mm can discriminate clinically meaningful changes in chronic cough severity in clinical studies.

Characterization of Patients With Refractory or Unexplained Chronic Cough Participating in a Phase 2 Clinical Trial of the P2X3-Receptor Antagonist Gefapixant.

PURPOSE: This analysis assesses clinical characteristics of patients with refractory chronic cough (RCC) or unexplained chronic cough (UCC) enrolled in a phase 2 study to better understand this patient population. METHODS: Patients with RCC/UCC lasting for ≥ 1 year and cough severity visual analog scale (VAS) score of > 40 mm at screening were eligible. Demographics, clinical characteristics, and medical history were collected at baseline. Cough-related measures included cough severity VAS, Cough Severity Diary (CSD), Leicester Cough Questionnaire (LCQ), and a structured cough-trigger questionnaire. Medication history included all medications 30 days before screening and chronic cough treatments within 1 year before screening. Data were summarized using descriptive statistics. RESULTS: Patients (N = 253; female, 76%; mean age, 60 years) had severe (mean cough severity VAS, 57.5 mm) and long-lasting (median duration, 11 years) cough. The most burdensome self-reported aspects included psychological and social factors (LCQ) and cough frequency and intensity (CSD). Patient-reported triggers were consistent with cough hypersensitivity (e.g., 95% to 96% reported irritation or tickle in throat). Common reported comorbidities included gastroesophageal reflux disease (GERD; 56%), allergic rhinitis (47%), and asthma (30%); 12% of patients had been diagnosed with all 3 conditions. The most common prior medications included inhaled or oral steroids (21%), antihistamines (15%), and antacids (15%). CONCLUSION: Patients with RCC/UCC had severe, long-lasting, and burdensome cough with clinical features of cough hypersensitivity. Many patients had been diagnosed with GERD, allergic rhinitis, and asthma but had a persistent cough despite treatment of these conditions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02612610; registered November 20, 2015.

Quantitative measurement properties and score interpretation of the Cough Severity Diary in patients with chronic cough.

AIMS: The Cough Severity Diary (CSD) was developed in accordance with the FDA guidance for patient-reported outcome measures and is focused on capturing the patient's perception of cough in terms of frequency, intensity, and disruption due to their cough. The measure includes a series of seven items asking patients to rate the frequency (three items), intensity (two items), and disruptiveness (two items) of their cough. The instrument was designed to be completed daily before bedtime, has a recall period of 'today,' and responses to items are entered on an 11-point numeric rating scale ranging from 0 to 10 with anchors on each end. The objective of this analysis was to confirm the domain structure of the CSD and assess its reliability, validity, and responsiveness in adult patients with refractory or unexplained chronic cough (RCC/UCC). Criteria for defining meaningful changes in mean weekly CSD total and domain scores in the context of a clinical trial were also developed. METHODS: Pooled data from a phase II randomized controlled trial of an investigational treatment for RCC/UCC were analyzed. Participants were non-smokers, had RCC/UCC for ⩾1 year, and a baseline cough severity visual analogue scale (VAS) ⩾40 mm. CSD scores (baseline, week 4), were analyzed; the Leicester Cough Questionnaire (LCQ), cough severity VAS, Patient Global Impression of Change (PGIC), and objective cough frequency counts were used for validation. CSD domain structure (Total, Frequency, Intensity, Disruption) was assessed for scoring. RESULTS: A total of 253 participants were included (mean age 60.2; 76% female). Global fit of the three-factor CSD was acceptable. For the CSD total score, internal consistency (α = 0.89) and test-retest reliability (intraclass correlation coefficient = 0.68) were high. CSD total scores were correlated with the LCQ total (r = -0.62) and cough severity VAS (r = 0.84). Participants with a PGIC score of 1 or 2 (most improved groups) had the greatest mean score improvement on the CSD Total (Day 0 to Day 28), supporting responsiveness (similar findings for subscales). A change threshold of ⩾1.3-point reduction on the total and subscale scores is appropriate to define clinically meaningful improvement. CONCLUSION: The CSD is a reliable, valid, and responsive measure of cough symptom severity in patients with refractory or unexplained chronic cough and fit-for-purpose for assessing changes in cough severity in clinical trials. The reviews of this paper are available via the supplemental material section.

Does recall period matter? Comparing PROMIS® physical function with no recall, 24-hr recall, and 7-day recall.

PURPOSE: To evaluate the influence of recall periods on the assessment of physical function, we compared, in cancer and general population samples, the standard administration of PROMIS Physical Function items without a recall period to administrations with 24-hour and 7-day recall periods. METHODS: We administered 31 items from the PROMIS Physical Function v2.0 item bank to 2400 respondents (n = 1001 with cancer; n = 1399 from the general population). Respondents were randomly assigned to one of three recall conditions (no recall, 24-hours, or 7-days) and one of two "reminder" conditions (with recall periods presented only at the start of the survey or with every item). We assessed items for potential differential item functioning (DIF) by recall time period. We then tested recall and reminder effects with analysis of variance controlling for demographics, English fluency, and co-morbidities. RESULTS: Based on conservative pre-set criteria, no items were flagged for recall time period-related DIF. Using analysis of variance, each condition was compared to the standard PROMIS administration for Physical Function (no recall period). There was no evidence of significant differences among groups in the cancer sample. In the general population sample, only the 24-hour recall condition with reminders was significantly different from the "no recall" PROMIS standard. At the item level, for both samples, the number of items with non-trivial effect size differences across conditions was minimal. CONCLUSIONS: Compared to no recall, the use of a recall period has little to no effect upon PROMIS physical function responses or scores. We recommend that PROMIS Physical Function be administered with the standard PROMIS "no recall" period.

Comparative analysis of the effects of nomegestrol acetate/17 ß-estradiol and drospirenone/ethinylestradiol on premenstrual and menstrual symptoms and dysmenorrhea.

OBJECTIVES: To compare premenstrual and menstrual symptoms in healthy women using nomegestrol acetate/17ß-estradiol (NOMAC/E2) and drospirenone/ethinylestradiol (DRSP/EE) via the Moos Menstrual Distress Questionnaire Form C (MDQ-C). METHODS: Women completed the MDQ-C at baseline and after completion of cycles 1, 3, 6 and 13, for the premenstrual (four days before most recent flow) and menstrual (most recent flow) phases in two randomized controlled trials. Treatment effects of NOMAC/E2 and DRSP/EE on the t-scores of eight MDQ-C symptom domains from 3522 women were examined, and the effects of both treatments on the score for cramps from 1779 women with moderate to severe cramps at baseline. Longitudinal data analysis methods were applied in both analyses. RESULTS: NOMAC/E2 users experienced a significant improvement in Pain, Water Retention, Negative Affect, Impaired Concentration and Behaviour Change domain scores in the menstrual phase compared with DRSP/EE users (p < 0.001 for all comparisons). However, Arousal (emotional and mental) scores worsened with NOMAC/E2 but not with DRSP/EE. Women with moderate to severe cramps experienced an improvement in the cramps score with NOMAC/E2 and DRSP/EE. CONCLUSIONS: NOMAC/E2 was effective in reducing most premenstrual and menstrual symptoms, and was associated with significantly greater improvements in many MDQ-C domain scores compared with DRSP/EE. ( ClinicalTrials.gov: NCT00413062 and NCT00511199).

Energy content of weight loss: kinetic features during voluntary caloric restriction.

The classic rule stating that restricting intake by 3500 kcal/wk will lead to a 1-lb/wk rate of weight loss has come under intense scrutiny. Generally not a component of most weight loss prediction models, the "early" rapid weight loss phase may represent a period during which the energy content of weight change (ΔEC/ΔW) is low and thus does not follow the classic "rule." The current study tested this hypothesis. Dynamic ΔEC/ΔW changes were examined in 23 Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Study overweight men and women evaluated by dual-energy x-ray absorptiometry during weight loss at treatment weeks 4 to 24. Changes from baseline in body energy content were estimated from fat and fat-free mass. Repeated-measures analysis of variance was used to determine if ΔEC/ΔW changed significantly over time. The evaluation was expanded with addition of the Kiel 13-week weight loss study of 75 obese men and women to test with adequate power if there are sex differences in ΔEC/ΔW. The analysis of variance CALERIE time effect was significant (P < .001), with post hoc tests indicating that ΔEC/ΔW (kilocalories per kilogram) increased significantly from week 4 (X ± SEM; 4, 858 ± 388) to 6 (6, 041 ± 376, P < .01) and changed insignificantly thereafter; ΔEC/ΔW was significantly larger for Kiel women (6, 804 ± 226) vs men (6, 119 ± 240, P < .05). Sex-specific dynamic relative changes in body composition and related ΔEC/ΔW occur with weight loss initiation that extend for 1 month or more. These observations provide new information for developing energy balance models and further define limitations of the 3500-kcal energy deficit → 1-lb weight loss rule.

Body circumferences: clinical implications emerging from a new geometric model.

BACKGROUND: Body volume expands with the positive energy balance associated with the development of adult human obesity and this "growth" is captured by two widely used clinical metrics, waist circumference and body mass index (BMI). Empirical correlations between circumferences, BMI, and related body compartments are frequently reported but fail to provide an important common conceptual foundation that can be related to key clinical observations. A two-phase program was designed to fill this important gap: a geometric model linking body volume with circumferences and BMI was developed and validated in cross-sectional cohorts; and the model was applied to the evaluation of longitudinally monitored subjects during periods of voluntary weight loss. Concepts emerging from the developed model were then used to examine the relations between the evaluated clinical measures and body composition. METHODS: Two groups of healthy adults (n = 494 and 1499) were included in the cross-sectional model development/testing phase and subjects in two previous weight loss studies were included in the longitudinal model evaluation phase. Five circumferences (arm, waist, hip, thigh, and calf; average of sum, C), height (H), BMI, body volume (V; underwater weighing), and the volumes of major body compartments (whole-body magnetic resonance imaging) were measured. RESULTS: The evaluation of a humanoid geometric model based a cylinder confirmed that V derived from C and H was highly correlated with measured V [R2 both males and females, 0.97; p < 0.001). Developed allometric models confirmed model predictions that C and BMI (represented as V/H) are directly linked as, C = (V/H)0.5. The scaling of individual circumferences to V/H varied, with waist the highest (V/H~0.6) and calf the lowest (V/H~0.3), indicating that the largest and smallest between-subject "growth" with greater body volume occurs in the abdominal area and lower extremities, respectively. A stepwise linear regression model including all five circumferences2 showed that each contributed independently to V/H. These cross-sectional observations were generally confirmed by analysis of the two longitudinal weight loss studies. The scaling of circumference ratios (e.g., waist/hip) to V/H conformed to models developed on the scaling of individual circumferences to V/H, indicating their relations to BMI are predictable a priori. Waist, hip, and arm/calf circumferences had the highest associations with whole-body visceral adipose tissue, subcutaneous adipose tissue, and skeletal muscle volumes, respectively. CONCLUSION: These observations provide a simple geometric model relating circumferences with body size and composition, introduce a conceptual foundation explaining previous empirical observations, and reveal new clinical insights.