Purpose

Efficient analytical methods are necessary to make reproducible inferences on single-item longitudinal ordinal patient-reported outcome (PRO) data. A thorough simulation study was performed to compare the performance of the semiparametric probabilistic index models (PIM) with a longitudinal analysis using parametric cumulative logit mixed models (CLMM).

Methods

In the setting of a control and intervention arm, we compared the power of the PIM and CLMM to detect differences in PRO adverse event (AE) between these groups using several existing and novel summary scores of PROs. For each scenario, PRO data were simulated using copula multinomial models. Comparisons were also exemplified using clinical trial data.

Results

On average, CLMM provided substantially greater power than the PIM to detect differences in PRO-AEs between the groups when the baseline-adjusted method was used, and a small advantage in power when using the baseline symptom as a covariate.

Conclusion

Although the CLMM showed the best performance among analytical methods, it relies on assumptions difficult to verify and that might not be fulfilled in the real world, therefore our recommendation is the use of PIM models with baseline symptom as a covariate.

Background

Graphical displays and data visualization are essential components of statistical analysis that can lead to improved understanding of clinical trial adverse event (AE) data. Correspondence analysis (CA) has been introduced decades ago as a multivariate technique that can communicate AE contingency tables using two-dimensional plots, while quantifying the loss of information as other dimension reduction techniques such as principal components and factor analysis.

Methods

We propose the application of stacked CA using contribution biplots as a tool to explore differences in AE data among treatments in clinical trials. We defined five levels of refinement for the analysis based on data derived from the Common Terminology Criteria for Adverse Events (CTCAE) grades, domains, terms and their combinations. In addition, we developed a Shiny app built in an R-package, visae, publicly available on Comprehensive R Archive Network (CRAN), to interactively investigate CA configurations based on the contribution to the explained variance and relative frequency of AEs. Data from two randomized controlled trials (RCT) were used to illustrate the proposed methods: NSABP R-04, a neoadjuvant rectal 2 × 2 factorial trial comparing radiation therapy with either capecitabine (Cape) or 5-fluorouracil (5-FU) alone with or without oxaliplatin (Oxa), and NSABP B-35, a double-blind RCT comparing tamoxifen to anastrozole in postmenopausal women with hormone-positive ductal carcinoma in situ.

Results

In the R04 trial (n = 1308), CA biplots displayed the discrepancies between single agent treatments and their combinations with Oxa at all levels of AE classes, such that these discrepancies were responsible for the largest portion of the explained variability among treatments. In addition, an interaction effect when adding Oxa to Cape/5-FU was identified when the distance between Cape+Oxa and 5-FU + Oxa was observed to be larger than the distance between 5-FU and Cape, with Cape+Oxa and 5-FU + Oxa in different quadrants of the CA biplots. In the B35 trial (n = 3009), CA biplots showed different patterns for non-adherent Anastrozole and Tamoxifen compared with their adherent counterparts.

Conclusion

CA with contribution biplot is an effective tool that can be used to summarize AE data in a two-dimensional display while minimizing the loss of information and interpretation.

Purpose

The US National Cancer Institute Moonshot initiative calls for improving analysis and reporting of toxicity to inform treatment tolerability. We used existing clinician-reported adverse event (AE) and patient-reported outcome (PRO) questionnaire data from the randomized, double-blind NSABP B-35 clinical trial to explore reasons for anastrozole and tamoxifen discontinuation.

Methods

Postmenopausal women with ductal carcinoma in situ treated with breast-conserving therapy were randomly assigned to anastrozole or tamoxifen for 5 years. The primary outcome for this analysis was time to treatment discontinuation. AEs were collected every 6 months post-random assignment from all 3,104 participants and summarized using the Toxicity Index (TI). PRO data were collected at baseline and every 6 months from 1,194 participants. Univariate and multivariable analyses of time to treatment discontinuation were performed using Cox regression models with TIs and PROs as time-dependent covariates.

Results

Of 3,046 analyzed participants, 869 (28.5%) discontinued treatment prematurely. In multivariable analysis, when both baseline PROs and on-treatment AEs were considered, thrombosis and arthralgia AEs were associated with discontinuation of both tamoxifen and anastrozole; additional AEs associated with discontinuation varied by drug. In addition, baseline pain interference, hot flashes, and unhappiness were associated with tamoxifen discontinuation (n = 589; overall Harrell's C-statistic 0.686 [95% CI, 0.640 to 0.732]); no baseline PROs were associated with anastrozole discontinuation (n = 589; overall Harrell's C-statistic 0.656 [95% CI, 0.630 to 0.681]). When only baseline PROs were examined, pain interference, hot flashes, and unhappiness were associated with shorter time to discontinuation of tamoxifen; only hot flashes were associated with discontinuation of anastrozole.

Conclusion

Analysis of AEs using the TI yielded important insights into reasons for discontinuation of endocrine therapy that was enhanced by the addition of PRO baseline and treatment-emergent symptoms.

Adjuvant chemotherapy improves breast cancer survival but is associated with bothersome short- and long-term toxicity. Factors associated with toxicity, especially subacute toxicity up to 2 years following chemotherapy, have not been fully elucidated. The NRG Oncology/NSABP B-30 clinical trial compared 3 different doxorubicin-, cyclophosphamide-, and docetaxel-based chemotherapy regimens given over 3-6 months. Patients with hormone receptor-positive breast cancer received subsequent adjuvant endocrine therapy. From baseline through 24 months, 2156 patients completed questionnaires serially. We used multivariable probabilistic index models to identify factors associated with acute (>0-12 months) and subacute (>12-24 months) difficulties with pain, cognition, vasomotor symptoms, and vaginal symptoms. For all symptom domains, presence of symptoms prior to chemotherapy initiation were associated with symptoms in the subacute period (all p < 0.001). In addition, different combinations of patient factors and breast cancer treatments were associated with increased likelihood of pain, vasomotor, and vaginal symptoms in the subacute period. Consideration of pre-treatment symptoms and patient factors, as well as treatments for breast cancer, can facilitate identification of groups of patients that may experience symptoms following completion of chemotherapy. This information may be important for treatment-decision-making when alternative regimens are equivalent in benefit.

Diffuse large B cell lymphoma (DLBCL) is an aggressive but potentially curable malignancy; however, cure is highly dependent on the ability to deliver intensive, anthracycline-based chemoimmunotherapy. Nearly one third of cases of DLBCL occur in patients over age 75 years, and advanced age is an important adverse feature in prognostic models. Despite this incidence in older patients, there is no clear accepted standard of care due to under-representation of this group in large randomized clinical trials. Furthermore, insufficient assessments of baseline frailty and prediction of toxicity hamper clinical decision-making. Here, we present an ongoing randomized study of R-miniCHOP chemoimmunotherapy with or without oral azacitidine (CC-486, Onureg) for patients age 75 and older with newly diagnosed DLBCL and associated aggressive lymphomas. The incorporation of an oral hypomethylating agent is based on increased tumor methylation as a biologic feature of older patients with DLBCL and a desire to minimize the injection burden for this population. This is the first randomized study in this population conducted in North America by the National Clinical Trials Network (NCTN) and will enroll up to 422 patients including 40 patients in a safety run-in phase. This study incorporates an objective assessment of baseline frailty (the FIL Tool) and a serial comprehensive geriatric assessment (CGA). Key correlative tests will include circulating tumor DNA (ctDNA) assays at pre-specified timepoints to explore if ctDNA quantity and methylation patterns correlate with response. S1918 has the potential to impact future trial design and to change the standard of care for patients 75 years and older with aggressive lymphoma given its randomized design, prospective incorporation of geriatric assessments, and exploration of ctDNA correlatives. Trial registration: The trial is registered with ClinicalTrial.gov Identifier NCT04799275.

Objective & methods: This study tested associations of genotype-predicted activity of CYP3A4, other pharmacogenes, SLC28A7 (rs11648166) and ALPPL2 (rs28845026) with systemic concentrations of the endocrine therapies anastrozole and fulvestrant in SWOG S0226 trial participants. Results: Participants in the anastrozole-only arm with low CYP3A4 activity (i.e. CYP3A4*22 carriers) had higher systemic anastrozole concentrations than patients with high CYP3A4 activity (β-coefficient = 10.03; 95% CI: 1.42, 18.6; p = 0.025). In an exploratory analysis, participants with low CYP2C9 activity had lower anastrozole concentrations and higher fulvestrant concentrations than participants with high CYP2C9 activity. Conclusion: Inherited genetic variation in CYP3A4 and CYP2C9 may affect concentrations of endocrine therapy and may be useful to personalize dosing and improve treatment outcomes.