Remarks on the design and analyses of longitudinal studies for cancer patients with anorexia and weight loss

Abstract Longitudinal data serve an important role in understanding the cancer anorexia weight loss syndrome and in testing interventions to palliative and treat patients who develop this syndrome. The element of time and the interrelatedness of data points define longitudinal data and add to the richness of this type of data. However, longitudinal data can also give rise to non‐random, missing data that can lead to flawed conclusions. This paper discusses these issues and suggests practical considerations for design and analysis of longitudinal cancer anorexia weight loss studies

Physician-Reported Experience and Understanding of Adverse Event Attribution in Cancer Clinical Trials

Objectives: To report the results of a survey conducted among Mayo Clinic medical oncologists, hematologists, and cancer prevention specialists to better understand the current practice of determining whether an adverse event that a patient experience in a clinical trial is related to the drug under investigation, a process commonly known as attribution, as well as to formulate recommendations for an improved system. Patients and Methods: An electronic survey was developed and conducted (from August 2 through 29, 2017) among 165 medical oncologists, hematologists, and cancer prevention specialists at the 3 Mayo Clinic sites: Rochester, Minnesota; Scottsdale, Arizona; and Jacksonville, Florida. The survey included 21 items that queried clinicians about their clinical practice and trial experience, their training and process in adverse event attribution assignment, and their recommendations for improving the current attribution system. Results: Thirty-seven percent (61 of 165) of physicians responded to the survey. The median number of years in clinical practice was 15 (range, 1-64) and that of clinical trial experience 12. Eighty-nine percent (54 of 61) had served as a trial principal investigator. Only 15% (9 of 60) of responders reported having received any formal attribution training. Eighty percent (48 of 60) were confident about their ability to assign attribution. Seventy-five percent (45 of 60) consulted their colleagues or study chair when assigning attribution. Sixty-seven percent (40 of 60) recommended formal training to improve attribution accuracy. Conclusion: Very few clinical trialists in our survey received any formal training for adverse event attribution, yet most identified formal training as effective means to improve attribution accuracy. These data underscore an unmet need of formal adverse event attribution training among clinical trialists

Adverse Event Burden Score—A Versatile Summary Measure for Cancer Clinical Trials

This article introduces the adverse event (AE) burden score. The AE burden by treatment cycle is a weighted sum of all grades and AEs that the patient experienced in a cycle. The overall AE burden score is the total AE burden the patient experienced across all treatment cycles. AE data from two completed Alliance multi-center randomized double-blind placebo-controlled trials, with different AE profiles (NCCTG 97-24-51: 176 patients, and A091105: 83 patients), were utilized for illustration. Results of the AE burden score analyses corroborated the trials’ primary results. In 97-24-51, the overall AE burden for patients on the treatment arm was 2.2 points higher than those on the placebo arm, with a higher AE burden for patients who went off treatment early due to AE. Similarly, in A091105, the overall AE burden was 1.6 points higher on the treatment arm. On the placebo arms, the AE burden in 97-24-51 remained constant over time; and increased in later cycles in A091105, likely attributable to the increase in disease morbidity. The AE burden score enables statistical comparisons analogous to other quantitative endpoints in clinical trials, and can readily accommodate different trial settings, diseases, and treatments, with diverse AE profiles

Olanzapine for the Treatment of Advanced Cancer–Related Chronic Nausea and/or Vomiting

Importance: Nausea and vomiting, unrelated to chemotherapy, can be substantial symptoms in patients with advanced cancer. Objective: To evaluate the utility of olanzapine for treating chronic nausea/vomiting, unrelated to chemotherapy, in patients with advanced cancer. Design, setting, and participants: This study is a double-line, placebo-controlled, randomized clinical trial conducted from July 2017 through April 2019, with analysis conducted in 2019. Eligible participants were outpatients with advanced cancer who had persistent nausea/vomiting without having had chemotherapy or radiotherapy in the prior 14 days. Chronic nausea was present for at least 1 week (worst daily nausea numeric rating scores needed to be greater than 3 on a 0-10 scale). Interventions: Patients received olanzapine (5 mg) or a placebo, orally, daily for 7 days. Main outcomes and measures: Patient-reported outcomes were used for study end points. Data were collected at baseline and daily for 7 more days. The primary study end point (the change in nausea numeric rating scores from baseline to the last treatment day) and the study hypothesis were both identified prior to data collection. Results: A total of 30 patients (15 per arm) were enrolled; these included 16 women and 14 men who had a mean (range) age of 63 (39-79) years. Baseline median nausea scores, in all patients, were 9 out of 10 (range, 8-10). After 1 day and 1 week, the median nausea scores in the placebo arm were 9 out of 10 (range, 8-10) on both days, compared with the olanzapine arm scores of 2 out of 10 (range, 2-3) after day 1 and 1 out of 10 (range, 0-3) after 1 week. After 1 week of treatment, the reduction in nausea scores in the olanzapine arm was 8 points (95% CI, 7-8) higher than that of the placebo arm. The primary 2-sided end point P value was <.001. Correspondingly, patients in the olanzapine arm reported less emesis, less use of other antiemetic drugs, better appetite, less sedation, less fatigue, and better well-being. One patient, on the placebo, stopped treatment early owing to lack of perceived benefit. No patients receiving olanzapine reported excess sedation or any other adverse event. Conclusions and relevance: Olanzapine, at 5 mg/d, appeared to be effective in controlling nausea and emesis and in improving other symptoms and quality-of-life parameters in the study population. Trial registration: ClinicalTrials.gov Identifier: NCT03137121

supp_mat – Supplemental material for Application of multi-state models in cancer clinical trials

<p>Supplemental material, supp_mat for Application of multi-state models in cancer clinical trials by Jennifer G Le-Rademacher, Ryan A Peterson, Terry M Therneau, Ben L Sanford, Richard M Stone and Sumithra J Mandrekar in Clinical Trials</p

Genetic Predictors of Chemotherapy-Induced Peripheral Neuropathy from Paclitaxel, Carboplatin and Oxaliplatin: NCCTG/Alliance N08C1, N08CA and N08CB Study

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially permanent adverse effect of chemotherapeutic agents including taxanes such as paclitaxel and platinum-based compounds such as oxaliplatin and carboplatin. Previous studies have suggested that genetics may impact the risk of CIPN. We conducted genome-wide association studies (GWASs) for CIPN in two independent populations who had completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-CIPN20 assessments (a CIPN-specific 20-item questionnaire which includes three scales that evaluate sensory, autonomic, and motor symptoms). The study population N08Cx included 692 participants from three clinical trials (North Central Cancer Treatment Group (NCCTG) N08C1, N08CA, and N08CB) who had been treated with paclitaxel, paclitaxel plus carboplatin, or oxaliplatin. The primary endpoint for the GWAS was the change from pre-chemotherapy CIPN20 sensory score to the worse score over the following 18 weeks. Study population The Mayo Clinic Breast Disease Registry (MCBDR) consisted of 381 Mayo Clinic Breast Disease Registry enrollees who had been treated with taxane or platinum-based chemotherapy. The primary endpoint for the GWAS assessed was the earliest CIPN20 sensory score available after the completion of chemotherapy. In multivariate model analyses, chemotherapy regimen (p = 3.0 × 10−8) and genetic ancestry (p = 0.007) were significantly associated with CIPN in the N08Cx population. Only age (p = 0.0004) was significantly associated with CIPN in the MCBDR population. The SNP most associated with CIPN was rs56360211 near PDE6C (p =7.92 × 10−8) in N08Cx and rs113807868 near TMEM150C in the MCBDR (p = 1.27 × 10−8). Due to a lack of replication, we cannot conclude that we identified any genetic predictors of CIPN

Genetic Variations and Health-Related Quality of Life (HRQOL): A Genome-Wide Study Approach

Health-related quality of life (HRQOL) is an important prognostic patient-reported outcome in oncology. Because prior studies suggest that HRQOL is, in part, heritable, we performed a GWAS to elucidate genetic factors associated with HRQOL in breast cancer survivors. Physical and mental HRQOL were measured via paper surveys that included the PROMIS-10 physical and mental health domain scales in 1442 breast cancer survivors participating in the Mayo Clinic Breast Disease Registry (MCBDR). In multivariable regression analyses, age and financial concerns were significantly associated with global physical health (age: p = 1.6 × 10−23; financial concerns: p = 4.8 × 10−40) and mental health (age: p = 3.5 × 10−7; financial concerns: p = 2.0 × 10−69). Chemotherapy was associated with worse global mental health (p = 0.01). In the GWAS, none of the SNPs reached the genome-wide association significance threshold of 5 × 10−8 for associations with either global physical or global mental health, however, a cluster of SNPs in SCN10A, particularly rs112718371, appeared to be linked to worse global physical health (p = 5.21 × 10−8). Additionally, SNPs in LMX1B, SGCD, PARP12 and SEMA5A were also moderately associated with worse physical and mental health (p −6). These biologically plausible candidate SNPs warrant further study as possible predictors of HRQOL

Genetic Predictors of Chemotherapy-Induced Peripheral Neuropathy from Paclitaxel, Carboplatin and Oxaliplatin: NCCTG/Alliance N08C1, N08CA and N08CB Study

Chemotherapy-induced peripheral neuropathy (CIPN) is a common and potentially permanent adverse effect of chemotherapeutic agents including taxanes such as paclitaxel and platinum-based compounds such as oxaliplatin and carboplatin. Previous studies have suggested that genetics may impact the risk of CIPN. We conducted genome-wide association studies (GWASs) for CIPN in two independent populations who had completed European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-CIPN20 assessments (a CIPN-specific 20-item questionnaire which includes three scales that evaluate sensory, autonomic, and motor symptoms). The study population N08Cx included 692 participants from three clinical trials (North Central Cancer Treatment Group (NCCTG) N08C1, N08CA, and N08CB) who had been treated with paclitaxel, paclitaxel plus carboplatin, or oxaliplatin. The primary endpoint for the GWAS was the change from pre-chemotherapy CIPN20 sensory score to the worse score over the following 18 weeks. Study population The Mayo Clinic Breast Disease Registry (MCBDR) consisted of 381 Mayo Clinic Breast Disease Registry enrollees who had been treated with taxane or platinum-based chemotherapy. The primary endpoint for the GWAS assessed was the earliest CIPN20 sensory score available after the completion of chemotherapy. In multivariate model analyses, chemotherapy regimen (p = 3.0 × 10−8) and genetic ancestry (p = 0.007) were significantly associated with CIPN in the N08Cx population. Only age (p = 0.0004) was significantly associated with CIPN in the MCBDR population. The SNP most associated with CIPN was rs56360211 near PDE6C (p =7.92 × 10−8) in N08Cx and rs113807868 near TMEM150C in the MCBDR (p = 1.27 × 10−8). Due to a lack of replication, we cannot conclude that we identified any genetic predictors of CIPN