Patient-Reported Outcomes Version Of The Common Terminology Criteria For Adverse Events Research Articles

Abstract PS02-02: Patient-reported outcomes from the Phase 3 CAPItello-291 trial investigating capivasertib and fulvestrant for patients with aromatase inhibitor-resistant HR-positive/HER2-negative advanced breast cancer

Abstract Background: In the Phase 3 CAPItello-291 trial, adding capivasertib (C), a pan-AKT inhibitor, to fulvestrant (F) in patients (pts) with aromatase inhibitor-resistant, HR+/HER2− (HER2− defined as IHC 0, or 1+ or IHC2+/ISH–) advanced breast cancer significantly improved PFS vs placebo (P) + F in the overall (HR 0.60, 95% CI 0.51, 0.71, p< 0.001) and AKT pathway-altered populations (HR 0.50, 95% CI 0.38, 0.65, p< 0.001). The safety profile of C-F was manageable; diarrhea (mostly grade 1) was the most frequent adverse event. Global health status (GHS)/health-related quality of life (HRQoL) was maintained from baseline in both arms; time to deterioration (TTD) favored C-F. We report results from additional patient-reported outcomes (PRO). Methods: Pts were randomized 1:1 to receive F (500 mg IM on days 1 and 15 of cycle 1 and day 1 of each subsequent 28-day cycle) with either P or C (400 mg BID; 4 days on, 3 days off). PRO measures assessed HRQoL, disease-related symptoms, functioning, and patient-reported treatment tolerability using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), EORTC QLQ Breast Cancer 23 items (EORTC QLQ-BR23), PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and Patient Global Impression of Treatment Tolerability (PGI-TT). PROs were assessed at pre-specified timepoints. Change from baseline was assessed using Mixed Model Repeat Measures (on-treatment scores) for EORTC QLQ-C30 and summarized for EORTC QLQ-BR23; TTD was assessed using the stratified log-rank test for both. Results: Overall, 708 pts were randomized to C-F (n=355) or P-F (n=353). Overall compliance rates with EORTC QLQ-C30 and PGI-TT were 84.5% and 80.6% with C-F and 81.8% and 81.7% with P-F, respectively. Baseline compliance rates with the EORTC QLQ-C30 and PGI-TT were 88.2% and 82.8% with C-F and 87.3% and 83.1% with P-F, respectively. Mean changes from baseline in EORTC QLQ-C30 functional and symptom domain scores were maintained with C-F and P-F, except for diarrhea in the C-F arm, where scores worsened by >10 points (table). TTD analysis showed that HRs favored C-F vs P-F for all functional and symptom domains, except diarrhea (HR 2.75; 95% CI 2.01, 3.81), which favored P-F (table). Median TTD of diarrhea was shorter with C-F vs P-F in line with the C-F safety profile. Diarrhea with C-F was generally manageable, and discontinuations due to diarrhea were low (2.0%; n=7/355). For PGI-TT, most pts reported that they were ‘not at all’ or ‘a little bit’ bothered by the side effects of cancer therapy. Over the first 6 months, the proportion of pts reporting to be ‘somewhat’, ‘quite a bit’, or ‘very much’ bothered by side effects was higher for C-F vs P-F, with between-arm differences being highest in the first 2 cycles. Results from EORTC QLQ-BR23 domains will be presented at the meeting. Conclusions: Pts treated with C-F maintained HRQoL for longer than pts treated with P-F on all EORTC QLQ-C30 functional and symptom domain scores, except diarrhea. Worsening of diarrhea was observed with C-F, consistent with the safety profile of C, but events appeared tolerable and did not negatively impact GHS/HRQoL. Together with the clinical efficacy and manageable safety profile of C-F, the PRO results from the CAPItello-291 trial further support a positive benefit–risk profile of the combination in this population. https://clinicaltrials.gov/: NCT04305496. Funding: CAPItello-291 is sponsored by AstraZeneca. Editorial acknowledgment: AstraZeneca-funded medical writing support was provided by Suzanne Patel, Ph.D., from BOLDSCIENCE Inc. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). Citation Format: Hope Rugo, Mafalda Oliveira, Sacha Howell, Florence Dalenc, Javier Cortés, Henry Gómez, Xichun Hu, Komal Jhaveri, Petr Krivorotko, Sibylle Loibl, Serafin Morales Murillo, Meena Okera, Yeon Park, Joo Hyuk Sohn, Eriko Tokunaga, Masakazu Toi, Samih Yousef, Lyudmila Zhukova, Marta Fulford, Haylee Andrews, Ian Wadsworth, Celina D’Cruz, Nicholas Turner. Patient-reported outcomes from the Phase 3 CAPItello-291 trial investigating capivasertib and fulvestrant for patients with aromatase inhibitor-resistant HR-positive/HER2-negative advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS02-02.

Development and initial validation of the AL-PROfile patient-reported outcome measure in light chain (AL) amyloidosis.

To evaluate the psychometric properties of the AL-PROfile, a patient-reported outcome measure combining the Patient-Reported Outcomes Measurement Information System (PROMIS)-29, two items from PROMIS Cognitive Function, and select Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) items. Content validity was assessed through cognitive debriefing interviews of 20 patients who completed the AL-PROfile (Study 1). Study 2 involved 297 participants who completed the AL-PROfile and Medical Outcomes Study 36-item Short-Form Health Survey (SF-36). Reliability (internal consistency and test-retest reliability) and validity (convergent and discriminant validity, known groups validity by stage/organ involvement) were calculated. Study 1 participants found the AL-PROfile straightforward confirming the relevance of the included content. Some felt that certain questions were not related to their amyloidosis experience. Study 2 demonstrated acceptable internal consistency for all domains/items except PROMIS Cognitive Function and acceptable test-retest reliability for all except PROMIS Cognitive Function and PRO-CTCAE nausea. Large correlations were seen for the same domain across measures while correlations for divergent domains within a measure and different domains across different measures were small. The PRO-CTCAE items showed small to medium correlations with each other and with PROMIS and SF-36 domains. Stage was associated with physical function, fatigue, social roles, swelling, and shortness of breath scores. The AL-PROfile has acceptable reliability and validity for use in systemic light chain amyloidosis patients.

Exploring a Mechanism Toward Automated Feedback for Cancer Patient Self-Reporting.

"Infobuttons" spearheaded electronic health records (EHR) based decision support by offering automated knowledge resources to physicians. However, how such a mechanism could be leveraged to provide optimal resources to patients remains unanswered. Informatics approaches are expected to utilize more relevant information beyond EHR, such as patient-reported outcomes, to support clinical decisions. This pilot study is intended to explore how patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE) in EHR can be incorporated and how to recommend tailored content to cancer patients via automated feedback.

Use of the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events to assess treatment tolerability in pulmonary arterial hypertension: qualitative patient research findings in current and former users of oral selexipag

BackgroundUnderstanding patients’ perspectives regarding drug tolerability, in addition to effectiveness, provides a complete picture of the patient experience and supports more informed therapeutic decision-making. The item library of the National Cancer Institute’s Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) was developed to measure patient-reported frequency, severity, and interference of adverse events (AEs) associated with cancer therapies. This qualitative interview study assessed the suitability of items selected from the PRO-CTCAE library for assessing tolerability of selexipag, a medication targeting the prostacyclin pathway for patients with pulmonary arterial hypertension (PAH).MethodsTwo rounds of 10 qualitative, web-assisted telephone interviews following a semi-structured guide were conducted in individuals with recent experience taking oral selexipag for PAH. Each interview included concept elicitation to gather participants’ perspectives on symptomatic AEs (type, frequency, severity, and interference) and cognitive debriefing of PRO-CTCAE items addressing the most frequently reported AEs of oral selexipag.ResultsInterviews were conducted with 20 participants with PAH (mean [range] age 50 [24–68] years; 75% female; 85% in World Health Organization Functional Class II–III), comprising different races/ethnicities, levels of education, and employment status. Fifteen participants were currently treated with selexipag; five had taken selexipag for ≥ 6 months before discontinuing. The most frequently reported AEs included headache, jaw pain, and nausea (n = 15, 12, and 10 participants, respectively). Diarrhea and headache were identified as the most bothersome AEs by 5 and 4 participants, respectively. Some AEs were transitory (e.g., jaw pain); others were long-lasting (e.g., muscle pain). Based on findings from Round 1 interviews, a flushing item was added and the PRO-CTCAE general pain item was modified to be specific to jaw pain for testing in Round 2. Interview findings identified the following AEs as relevant to assess in a PAH clinical trial: nausea, vomiting, diarrhea, flushing, jaw pain, headache, aching muscles, and aching joints.ConclusionsThe PRO-CTCAE items selected in this study and the additional symptomatic AEs identified as patient-relevant have the potential to be included in assessments capturing the patient perspective on tolerability in future studies of selexipag and possibly other PAH therapies.

Abstract C067: Patient-reported baseline symptomatic adverse events in early-phase trials of combination treatments with immune checkpoint blockade, and their association with concurrent global health status, health utilities and clinical factors

Abstract Background: We examined patient-reported symptomatic adverse events (AEs) prior to trial start, and their association with concurrent global health status, health utilities and clinical factors in patients enrolled in early-phase trials combining immune checkpoint blockade with other anticancer therapy. Methods: Within 2 weeks prior to trial start, patients consented to begin an early phase trial of a combination treatment including at least 1 immune checkpoint inhibitor completed validated items of the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) measuring severity and/or frequency of selected symptomatic adverse events (score range: 0-4, higher scores=worse severity/increased frequency) in the last 7 days. Patients also completed the validated EuroQoL-5 dimensions questionnaire measuring global health status (score range: 0-100, higher scores=better health status) and health utilities (e.g., problems with self-care, mobility). Clinical data were extracted from the EMR. Statistical tests included χ2 and Spearman’s correlations. Results: 206 patients (median age=59y; 54% male; 84% White) from 54 early-phase trials participated. Prevalent moderate-to-severe symptomatic AEs at baseline prior to trial start included fatigue (43% of patients), decreased sexual interest (24%), appetite loss (21%), dry mouth (17%) and shortness of breath (16%). Frequent-to-almost constant general pain, abdominal pain and nausea were reported by 27%, 13% and 5% of patients, respectively. Worse fatigue, and more frequent general pain and abdominal pain were associated with diminished global health status (P<0.001 for each). Worse fatigue was also linked to problems with mobility, self-care, anxiety, and usual activities (P<0.001 for each), and to lower concurrent lymphocyte counts (P=0.002), hemoglobin (P=0.002) and serum albumin (P=0.029). Loss of appetite was related to lower lymphocytes (P=0.005), platelets (P=0.011), and serum albumin (P=0.021) and higher neutrophils (P=023). Dyspnea was linked to lower albumin (P=0.014). Loss of sexual interest was associated with worse pain (P<0.001), anxiety (P=0.011), and problems with usual activities (P<0.001), lower serum albumin (0.005), lymphocytes (P=0.010), hemoglobin (0.019), and creatinine (P=0.03) and higher neutrophils (P=0.009) and white blood cells (0.023). Conclusions: Patients in early-phase trials of combination treatments with an immune checkpoint inhibitor may report considerable moderate-to-severe symptomatic AEs, even at baseline. Patient-reported symptomatic AEs impact global health status, health utilities, and a constellation of clinical factors. Thus, it is critical in early-phase trials to baseline symptomatic AEs including from the patient’s perspective in order to more completely assess the impact of combination treatments that include a checkpoint inhibitor. Citation Format: Goldy C. George, Sarina A Piha-Paul, Siqing Fu, Ecaterina Dumbrava, Vivek Subbiah, Apostolia Tsimberidou, George Blumenschein, Shubham Pant, Grace Appleton, Laila Noor, Jordi Rodon Ahnert, Timothy Yap, Funda Meric-Bernstam, Charles Cleeland, Tito Mendoza, David S Hong. Patient-reported baseline symptomatic adverse events in early-phase trials of combination treatments with immune checkpoint blockade, and their association with concurrent global health status, health utilities and clinical factors [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr C067.

AHOD2131: A Randomized Phase 3 Response-Adapted Trial Comparing Standard Therapy with Immuno-Oncology Therapy for Children and Adults with Newly Diagnosed Stage I and II Classic Hodgkin Lymphoma

Background: Chemotherapy in combination with radiotherapy (RT) is the standard for early-stage (ES) Hodgkin lymphoma (cHL). Despite high cure rates (12-year overall survival (OS) >93%), there is room to improve short and long-term outcomes for children and adults with ES cHL. Incorporation of immunotherapy (IO) into front line treatment of ES cHL is an opportunity to both improve progression-free survival (PFS) and maintain OS, while minimizing long-term morbidity and mortality by reducing exposure to RT and high-dose chemotherapy. Study Design and Methods: HL leaders of the NCTN groups, expert HL researchers and physicians, and representatives from the Cancer Therapy Evaluation Program (CTEP) formed a working group in April 2020 with the goals of harmonizing treatment approaches for ES cHL across pediatric and adult patients and reaching consensus regarding the optimal study design for incorporating IO therapy into frontline treatment. Study champions identified from each of the North American cooperative groups [Children's Oncology Group (COG), SWOG, ECOG-ACRIN, Alliance, NRG] and experts in imaging, radiation oncology, lymphoma biology and patient-reported outcomes (PROs) were included. The resulting COG-led clinical trial, AHOD2131, represents the largest ES cHL trial in the history of North American cooperative groups and the first to enroll patients across the age continuum. AHOD2131 (NCT05675410; Figure) is a randomized, phase 3 trial enrolling patients ages 5 to 60 years with newly diagnosed, previously untreated stage I and II cHL and will investigate the addition of the CD30-antibody drug conjugate brentuximab vedotin (Bv) with PD-1 blockade (nivolumab) compared to standard chemotherapy +/- RT. Since the April 2023 activation, 97 North American sites have activated the trial, and 21 participants have enrolled. Target enrollment is 1875 patients over 5 years of accrual, for an estimated 1782 eligible and evaluable patients. The primary objective is to compare the 3-year PFS of patients with ES cHL treated through a response-adapted, superiority design with either standard therapy or with an IO approach (BV + nivolumab). All patients will be stratified as favorable or unfavorable based on disease risk features at enrollment. Based on initial response assessment by PET/CT (via central review) after 2 cycles of ABVD, patients were classified to PET2 positive (SER, defined as 5 Point Score 4 or 5, ~15% of patients) and PET negative (RER). Those who are PET positive will receive involved site RT (ISRT). The SER and RER patients will be randomized to standard chemotherapy vs. IO therapy respectively. In addition to the primary outcome of PFS, there are 11 secondary and 10 exploratory aims. The secondary aims focus on OS, PFS of subgroups, and event-free survival at 12 years, physician-reported treatment-related adverse event (AE) rates, patient-reported AE using pediatric and adult versions of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and the capture of representation by self-report and the use of electronic PRO data collections. The exploratory aims include the assessment of imaging central review as compared to local institutional review and the use of convolutional neural networks through artificial-intelligence machine learning. The study will examine the effect of therapy on acute and long-term adverse effects including health-related quality of life (HRQoL) and OS for up to 12 years. The study will compare patient self-report and provider AE reports and evaluate the associations of self-reported race/ethnicity and social determinants of health (SDOH)and post-progression/post-relapse OS. AHOD2131 strengthens the effort between the North American cooperative groups to conduct collaborative clinical trials and aims to harmonize an improved standard of care for ES cHL across the age continuum.

Evaluating Immune-Related Adverse Events Using PRO-CTCAE in a Phase II Study of Ipilimumab for Hormone-Sensitive Prostate Cancer.

Use of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) during chemotherapy is associated with decreased hospitalization rates, improved quality of life, and longer survival. Limited data exist on the benefit of this symptom assessment tool for monitoring immune-related adverse events (irAEs). We incorporated irAE-related items from the National Cancer Institute's (NCI) PRO-CTCAE in a trial evaluating ipilimumab in combination with androgen deprivation therapy in 16 patients with hormone-sensitive prostate cancer. For comparison, NCI's CTCAE version 4.0 was used by clinicians. IrAE-related PRO-CTCAE surveys and matched CTCAEs (184 pairs) reporting abdominal pain, diarrhea, fatigue, anorexia, nausea, vomiting, rash, and pruritus were collected at each treatment administration and during follow-up. Fatigue, diarrhea, rash, and pruritus were the symptoms most frequently reported by both patients and clinicians. Agreement was lowest for pruritus (κ = 0.10) and highest for rash (κ = 0.64). IrAEs were more commonly reported and of higher grade with PRO-CTCAE scores compared with CTCAE grades. PRO-CTCAEs focused on irAEs capture the patient's immunotherapy experience while complementing the clinician's toxicity assessment measures. Further study is needed to assess PRO-CTCAE's utility in identifying and managing irAEs.

Testing a Model of Care for Patients on Immune Checkpoint Inhibitors Based on Electronic Patient-Reported Outcomes: Protocol for a Randomized Phase II Controlled Trial.

Management of severe symptomatic immune-related adverse events (IrAEs) related to immune checkpoint inhibitors (ICIs) can be facilitated by timely detection. As patients face a heterogeneous set of symptoms outside the clinical setting, remotely monitoring and assessing symptoms by using patient-reported outcomes (PROs) may result in shorter delays between symptom onset and clinician detection. We assess the effect of a model of care for remote patient monitoring and symptom management based on PRO data on the time to detection of symptomatic IrAEs from symptom onset. The secondary objectives are to assess its effects on the time between symptomatic IrAE detection and intervention, IrAE grade (severity), health-related quality of life, self-efficacy, and overall survival at 6 months. For this study, 198 patients with cancer receiving systemic treatment comprising ICIs exclusively will be recruited from 2 Swiss university hospitals. Patients are randomized (1:1) to a digital model of care (intervention) or usual care (control group). Patients are enrolled for 6 months, and they use an electronic app to complete weekly Functional Assessment of Cancer Therapy-General questionnaire and PROMIS (PROs Measurement Information System) Self-Efficacy to Manage Symptoms questionnaires. The intervention patient group completes a standard set of 37 items in a weekly PROs version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) questionnaire, and active symptoms are reassessed daily for the first 3 months by using a modified 24-hour recall period. Patients can add items from the full PRO-CTCAE item library to their questionnaire. Nurses call patients in the event of new or worsening symptoms and manage them by using a standardized triage algorithm based on the United Kingdom Oncology Nursing Society 24-hour triage tool. This algorithm provides guidance on deciding if patients should receive in-person care, if monitoring should be increased, or if self-management education should be reinforced. The Institut Suisse de Recherche Expérimentale sur le Cancer Foundation and Kaiku Health Ltd funded this study. Active recruitment began since November 2021 and is projected to conclude in November 2023. Trial results are expected to be published in the first quarter of 2024 and will be disseminated through publications submitted at international scientific conferences. This trial is among the first trials to use PRO data to directly influence routine care of patients treated with ICIs and addresses some limitations in previous studies. This trial collects a wider spectrum of self-reported symptom data daily. There are some methodological limitations brought by changes in evolving treatment standards for patients with cancer. This trial's results could entail further academic discussions on the challenges of diagnosing and managing symptoms associated with treatment remotely by providing further insights into the burden symptoms represent to patients and highlight the complexity of care procedures involved in managing symptomatic IrAEs. ClinicalTrials.gov NCT05530187; https://www.clinicaltrials.gov/study/NCT05530187. DERR1-10.2196/48386.

Physician and Patient-Reported Outcomes of a Phase III Trial of Ultra-Hypofractionated vs. Moderate Hypofractionated Radiotherapy to the Whole Breast after Breast-Conserving Surgery

To report a final analysis evaluating physician and patient-reported outcomes of early breast cancer patients receiving moderate hypofractionation or ultra-hypofractionated whole breast radiotherapy (RT). Between April 4, 2018, and February 11, 2020, patients with localized breast cancer (T1-T3, N0-N1, and M0) managed with breast-conserving surgery (BCS) were enrolled. Patients were randomized to receive whole breast RT with moderate hypofractionation to 40 Gy in 15 fractions (Arm A) or ultra-hypofractionation to 25 Gy in 5 fractions (Arm B). An optional concurrent integrated boost to 48 Gy on Arm A or 30 Gy on Arm B was allowed. Early toxicity (<3 months), late toxicity (> 3 months), quality of life (QOL), cosmesis, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE), and deterioration of cosmesis were analyzed. One hundred and seven patients were randomized to moderate hypofractionation (n = 54) or ultra-hypofractionation (n = 53). With a median follow-up of 36 months, no significant differences in patient characteristics were noted between the two arms. There were no patients with a grade ≥3 or higher toxicity. Grade 2 toxicities were 7.4% in Arm A and 7.5% in Arm B, and primarily consisted of radiation dermatitis (6 patients), fibrosis (1 patient) and lymphedema (1 patient). The average Harvard Cosmesis score and overall QoL were similar between arms at all time points, with no patients developing cosmetic deterioration. Patient-reported moderate to severe radiation skin burns were more commonly reported in Arm A (21.05%) vs. Arm B (6.25%) at the end of treatment (EOT) (p = 0.078). At EOT, patients receiving moderate hypofractionation had higher mean toxicity scores in breast tenderness (2.66 vs. 1.5, p = 0.018), skin flaking or peeling (0.63 vs. 0.06, p = 0.035), blistering (0.74 vs. 0.06, p = 0.028), pruritis (2.53 vs. 0.87, p < 0.001), erythema (4.24 vs. 2.0, p <0.001), telangiectasias (1.0 vs. 0.28, p = 0.021). Additionally, patients receiving moderate hypofractionation reported significantly worse changes from baseline at EOT in breast tenderness (-2.25 vs. -.86, p = 0.02), telangiectasia (-0.81 vs. 0.18, p = 0.012), skin discoloration (-4.31 vs. -1.04, p < 0.001), skin flaking or peeling (-.55 vs. 0.04, p = 0.053), blistering (-0.82 vs. -0.07, p = 0.033), and pruritus (-2.27 vs. -.67, p = 0.002). There was a return to baseline in all patient-reported breast domains by 3 months (p >0.05) in both arms. Ultra-hypofractionated whole breast irradiation, consisting of 25 Gy in 5 fractions, provided comparable provider assessed toxicity and cosmetic outcomes to 40 Gy in 15 fractions. At the EOT assessment, ultra-hypofractionation had a better patient reported toxicity profile. Our findings provide further evidence to support daily ultra-hypofractionated whole breast radiotherapy as an appropriate treatment option for early-stage breast cancer.

Completion rates and trends of the patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) across 14 oncology clinical trials.

1579 Background: With growing emphasis on patient-centered regulatory decision making, there is a greater need to incorporate the patient’s voice in oncology clinical trials. Regulatory guidelines outline core patient-reported outcomes (PROs) to include which can inform risk/benefit evaluation. Self-reported symptomatic adverse events (AE) form part of these core PROs, with the new 2023 draft FDA guidance acknowledging the benefits of including them to enhance the assessment of tolerability in early phase dose optimization trials. Given the clinical symptoms and disease burden in oncology, patient burden needs to be thoughtfully considered when incorporating PROs into trials. We assessed trends and feasibility of electronic data collection for symptomatic AEs by analyzing completion compliance and time to complete the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) across 14 oncology trials. Methods: All PRO-CTCAE were collected electronically on Clario Tablets. Operational data for completion status (completed or missed) and duration of time to complete the PRO-CTCAE in seconds was extracted. Completion rates over time were examined overall and for every 3-month interval (quarters Q1 to Q9+). The median was selected for analyses of time to complete to account for skewness. Results: The sample included 14 studies across Phase I-III trials across a range of cancers including multiple myeloma, mesothelioma and cancers of the lung, prostate, head/neck, gastric, breast, and ovary. Study durations were 24 weeks and up. The PRO-CTCAE form was completed 13,122 times and missed in 1,182 instances, giving an overall completion rate of 91.7%. On average, 25 questions (range 5-47) covered an average of 13 symptoms (range: 4-25). Completion rate was not associated with the number of questions asked or time since enrollment. The overall median time to complete the PRO-CTCAE was 82s (study-specific median range: 24s to 276s). Examining time to completion as a function of the number of questions revealed a significant positive association, such that each additional question added 5.2 seconds to the time it took to complete the assessment. Conclusions: Completion compliance was high for PRO-CTCAE and remained high regardless of study length and the number of questions included in the PRO-CTCAE form. This suggests that electronic PRO-CTCAE is a feasible solution for collecting self-reported symptomatic AEs. Although time to complete the form increased with the number of questions, results suggest that including a higher number of PRO-CTCAE questions does not negatively impact compliance rate. Our data showing high completion rates may also reflect the benefits of electronic PROs in reducing patient burden and enhancing data quality, as acknowledged by regulatory agencies.

A Pilot Trial of Patient-Reported Outcomes for Acute Graft-Versus-Host-Disease

Acute graft-versus-host disease (GVHD) is a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Acute GVHD is associated with severe physical and psychosocial symptoms. We sought to evaluate the feasibility of capturing patient-reported outcome (PRO) measures in acute GVHD to better measure symptom burden and quality of life (QOL). We conducted a pilot study of adult patients undergoing first allogeneic HCT. Questions from Functional Assessment of Cancer Therapy-Bone Marrow Transplantation (FACT-BMT), Patient-Reported Outcomes Measurement Information System (PROMIS-10), and Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) were selected, and the survey was administered electronically before HCT, at days 14, 50, and 100 after HCT. In addition, patients who developed grade 2-4 acute GVHD received it weekly for 4 weeks and then monthly up to 3 months. From 2018 to 2020, 73 patients were consented, of which 66 went on to undergo HCT and were included in the analysis. Median age at transplantation was 63 years, and 92% were Caucasian. Only 47% of expected surveys were completed (range 0%-67% for each time point). Descriptive exploratory analysis demonstrate an expected trajectory of QOL using the FACT-BMT and PROMIS-10 scores throughout transplantation. Patients who developed acute GVHD (N=15) generally had lower QOL scores compared to those with no or mild GVHD post-HCT. The PRO-CTCAE captured several physical and mental/emotional symptoms in all patients and those with GVHD. Fatigue (100%), decreased appetite (92%), problem tasting (85%), loose stools (77%), pain (77%), skin itching (77%), and depression (feeling sad) (69%) were the most prevalent symptoms among patients with grade 2-4 acute GVHD. Patients with acute GVHD generally reported worse symptoms than those with no/mild GVHD in frequency, severity, and interference in normal activities. Several challenges were identified including poor access/literacy of electronic surveys, acute illness, and need for extensive research/resource support. We demonstrate the challenges yet potential of using PRO measures in acute GVHD. We demonstrate that the PROMIS-10 and PRO-CTCAE measures are able to capture several symptoms and QOL domains of acute GVHD. Further investigation into making PROs feasible in acute GVHD are needed.

Exploring differences in symptomatic adverse events assessment between nurses and physicians in the clinical trial setting

A cross-sectional study was performed at Hebei Medical University Fourth Affiliated Hospital from April to July 2020 to explore the difference and consistency between nurses and physicians in terms of symptomatic adverse event (AE) assessment. The Common Terminology Criteria for Adverse Events (CTCAE) was utilized by nurses and physicians to assess patients’ symptomatic AEs. Patients self-reported their AEs utilizing the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). Four nurses and three physicians were enrolled to assess patients’ symptomatic AEs. Given the same AEs, nurses tended to detect more AEs than physicians, and the differences were statistically significant (P < 0.001). The toxicity grade reported by nurses and physicians showed no difference for all AEs, except for fatigue (χ2 = 5.083, P = 0.024). The agreement between nurses and patients was highest compared to the agreement between nurses versus physicians and physicians versus patients. The differences in symptomatic AE assessment can lead to different symptom management. Thus, it is important to establish a collaborative approach between nurses and physicians to ensure continuity in care delivery.

An Unsupervised Machine Learning Approach to Evaluating the Association of Symptom Clusters With Adverse Outcomes Among Older Adults With Advanced Cancer

Older adults with advanced cancer who have high pretreatment symptom severity often experience adverse events during cancer treatments. Unsupervised machine learning may help stratify patients into different risk groups. To evaluate whether clusters identified from baseline patient-reported symptom severity were associated with adverse outcomes. This secondary analysis of the Geriatric Assessment Intervention for Reducing Toxicity in Older Patients With Advanced Cancer (GAP70+) Trial (2014-2019) included patients who completed the National Cancer Institute Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) before starting a new cancer treatment regimen and received care at community oncology sites across the United States. An unsupervised machine learning algorithm (k-means with Euclidean distance) clustered patients based on similarities of baseline symptom severities. Clustering variables included severity items of 24 PRO-CTCAE symptoms (range, 0-4; corresponding to none, mild, moderate, severe, and very severe). Total severity score was calculated as the sum of 24 items (range, 0-96). Whether the clusters were associated with unplanned hospitalization, death, and toxic effects was then examined. Analyses were conducted in January and February 2022. Symptom severity. Unplanned hospitalization over 3 months (primary), all-cause mortality over 1 year, and any clinician-rated grade 3 to 5 toxic effect over 3 months. Of 718 enrolled patients, 706 completed baseline PRO-CTCAE and were included (mean [SD] age, 77.2 [5.5] years, 401 [56.8%] male patients; 51 [7.2%] Black and 619 [87.8%] non-Hispanic White patients; 245 [34.7%] with gastrointestinal cancer; 175 [24.8%] with lung cancer; mean [SD] impaired Geriatric Assessment domains, 4.5 [1.6]). The algorithm classified 310 (43.9%), 295 (41.8%), and 101 (14.3%) into low-, medium-, and high-severity clusters (within-cluster mean [SD] severity scores: low, 6.3 [3.4]; moderate, 16.6 [4.3]; high, 29.8 [7.8]; P < .001). Controlling for sociodemographic variables, clinical factors, study group, and practice site, compared with patients in the low-severity cluster, those in the moderate-severity cluster were more likely to experience hospitalization (risk ratio, 1.36; 95% CI, 1.01-1.84; P = .046). Moderate- and high-severity clusters were associated with a higher risk of death (moderate: hazard ratio, 1.31; 95% CI, 1.01-1.69; P = .04; high: hazard ratio, 2.00; 95% CI, 1.43-2.78; P < .001), but not toxic effects. In this study, unsupervised machine learning partitioned patients into distinct symptom severity clusters; patients with higher pretreatment severity were more likely to experience hospitalization and death. ClinicalTrials.gov Identifier: NCT02054741.

A toolbox of different approaches to analyze and present PRO-CTCAE data in oncology studies.

The patient-reported outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is used to assess symptomatic adverse events in oncology trials. Currently, no standard for PRO-CTCAE analysis exists. Key methods of descriptive analysis and longitudinal modeling using PRO-CTCAE data from an oncology clinical trial, DRiving Excellence in Approaches to Multiple Myeloma-2 (DREAMM-2), a phase II trial of belantamab mafodotin in multiple myeloma (NCT03525678), were explored. Descriptive methods included maximum postbaseline ratings, mean change over time, ratings above a predefined cutoff, line graphs, and stacked bar charts to illustrate patient-reported adverse events at one timepoint or dynamics over time. Analysis methods involving modeling over time included toxicity over time (ToxT) (repeated measurement model, time-to-event, area under the curve analyses), generalized estimating equations (GEE), and ordinal log-linear models (OLLMs). Visualizations of PRO-CTCAE data highlighted different aspects of the data. Selection of the appropriate visualization will depend on the audience and message to be conveyed. Consistent results were obtained by all modeling approaches; no difference was found between dose groups of the DREAMM-2 study in any PRO-CTCAE item by the ToxT approach or the more sophisticated GEE and OLLM methods. Interpretation of GEE results was the most challenging. OLLM supported the interval nature of the PRO-CTCAE response scale in the DREAMM-2 study. All modeling approaches account for multiple testing (driven by the number of items). Descriptive analyses and longitudinal modeling approaches are complementary approaches to presenting PRO-CTCAE data. In modeling, the ToxT approach may be a good compromise compared with more sophisticated analyses.

Identifying symptomatic adverse events using the patient-reported outcomes version of the common terminology criteria for adverse events in patients with non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations.

Tolerability and safety of treatments are important in oncology trials and should be informed by patient assessments. We identified the most relevant patient-reported symptomatic adverse events (AEs) to measure in patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations. This study selected relevant symptomatic AEs from 78 AEs available in the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) measurement system. Initially, symptomatic AEs were selected based on literature and product labeling reviews, and then core sets of symptomatic AEs were identified by patient and clinician interviews. Qualitative and descriptive analyses were performed using the data collected from three iterative rounds of patient interviews. During concept elicitation interviews involving 29 patients, 12 symptomatic AEs were identified and were then adapted into a 25-item PRO-CTCAE form for use in future clinical trials along with commonly used PRO measures. Cognitive interviews showed that the PRO-CTCAE items were easy to answer and appropriate for assessing the patients' experience with symptomatic AEs. This study also assessed disease symptoms, impacts, and overall patient experience. The 25-item PRO-CTCAE form captures the most relevant symptomatic AEs in this patient population, and it is available for future studies. Baseline characterization of AEs associated with this distinct patient group contributes to our broader knowledge about NSCLC and through platforms like Project Patient Voice will expand our understanding of treatment tolerability and safety for NSCLC. Ultimately, this data collection will help inform decision-making for patients, caregivers, healthcare providers, and regulators.

Mobocertinib (TAK-788) in EGFR Exon 20 Insertion+ Metastatic NSCLC: Patient-Reported Outcomes from EXCLAIM Extension Cohort.

Mobocertinib, an oral, first-in-class epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor selective for EGFR exon 20 insertions (ex20ins), achieved durable responses in adults with previously treated EGFR ex20ins+ metastatic non-small cell lung cancer (mNSCLC) in the EXCLAIM extension cohort of a phase 1/2 study (N = 96; NCT02716116). We assessed patient-reported outcomes (PROs) with mobocertinib 160 mg once daily (28-day cycles) in EXCLAIM (N = 90) with the European Organisation for Research and Treatment of Cancer Core Quality-of-Life Questionnaire (EORTC QLQ-C30) v3.0, lung cancer module (QLQ-LC13), EuroQol-5 Dimensions-5 Levels (EQ-5D-5L) questionnaire, and selected PRO Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) questionnaire. Median treatment duration was 6.8 (range, 0.0-18.8) months (median follow-up: 13.0 [0.7-18.8] months; data cutoff: 1 November 2020). Clinically meaningful improvements in lung cancer symptoms measured by EORTC QLQ-LC13 were observed for dyspnea (54.4% of patients), cough (46.7%), and chest pain (38.9%), evident at cycle 2 and throughout treatment (least-squares mean [LSM] changes from baseline: dyspnea, -3.2 [p = 0.019]; cough, -9.3 [p < 0.001]; chest pain, -8.2 [p < 0.001]). EORTC QLQ-C30 results indicated no statistically significant changes in global health status/quality of life (LSM change from baseline: -1.8 [p = 0.235]). On symptom scores, significant worsening from baseline was observed for diarrhea (LSM change from baseline: +34.1; p < 0.001) and appetite loss (+6.6; p = 0.004), while improvements were observed for dyspnea (LSM change from baseline: -5.1 [p = 0.002]), insomnia (-6.5 [p = 0.001]), and constipation (-5.7 [p < 0.001]). EQ-5D-5L health status was maintained. Common PRO-CTCAE symptoms were diarrhea, dry skin, rash, and decreased appetite (mostly low grade); in the first 24 weeks of treatment, 64.4% of patients had worsening diarrhea frequency and 67.8% had worsening dry skin severity. Overall, PROs with mobocertinib showed clinically meaningful improvement in lung cancer-related symptoms, with health-related quality of life maintained despite changes in some adverse event symptom scales.

Outcomes of Proton Beam Therapy Compared With Intensity-Modulated Radiation Therapy for Uterine Cancer.

To compare Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in patients with endometrial cancer receiving adjuvant pelvic radiation therapy with proton beam therapy (PT) versus intensity-modulated radiation therapy (IMRT). Patients with uterine cancer treated with curative intent who received either adjuvant PT or IMRT between 2014 and 2020 were identified. Patients were enrolled into a prospective registry using a gynecologic-specific subset of PRO-CTCAE designed to assess symptom impact on daily living. Questions included gastrointestinal (GI) symptoms of diarrhea, flatulence, bowel incontinence, and constipation in addition to other pertinent gynecologic, urinary, and other general symptoms. Symptom-based questions were on a 0- to 4-point scale, with grade 3+ symptoms occurring frequently or almost always. Patient-reported toxicity was analyzed at baseline, end of treatment (EOT), and at 3, 6, 9, and 12 months after treatment. Unequal variance t tests were used to determine if treatment type was a significant factor in baseline-adjusted PRO-CTCAE. Sixty-seven patients met inclusion criteria. Twenty-two received PT and 45 patients received IMRT. Brachytherapy boost was delivered in 73% of patients. Median external beam dose was 45 Gy for both PT and IMRT (range, 45-58.8 Gy). When comparing PRO-CTCAE, PT was associated with less diarrhea at EOT (P = .01) and at 12 months (P = .24) than IMRT. Loss of bowel control at 12 months was more common in patients receiving IMRT (P = .15). Any patient reporting grade 3+ GI toxicity was noted more frequently with IMRT (31% versus 9%, P = .09). Adjuvant PT is a promising treatment for patients with uterine cancer and may reduce patient-reported GI toxicity as compared with IMRT.

Web-Based Symptom Monitoring with Patient-Reported Outcomes during Definitive Radiation Therapy with Chemotherapy (SYMPATHY): A Prospective Single-Center Phase I Study

<h3>Purpose/Objective(s)</h3> We evaluated the feasibility of patient symptom self-reporting using a web-based interface (WBI), with automated message alerts for severe or worsening symptoms, in patients undergoing definitive chemoradiation therapy (CRT). <h3>Materials/Methods</h3> Patients receiving definitive CRT for gastrointestinal, lung, and head and neck cancer with access to a computer/mobile device were eligible. Symptom self-reporting was conducted via a WBI through surveys adapted from the patient-reported outcomes version of the common terminology criteria for adverse events (PRO-CTCAE), 2/week during CRT and 1/week for 3 months post-CRT. Nurses were alerted whenever a patient's symptom worsened by ≥ 2 points or reached a score of ≥3. Patient-Reported Outcomes Measurement Information System (PROMIS) surveys were conducted at baseline, end of RT and 3 months post-RT. Patients also completed exit surveys 3 months post-CRT. <h3>Results</h3> Nineteen patients were enrolled with a median of 30 fractions (range 28-33). Median survey completion rate was 26% (range 0-100%) during CRT and 33% (range 0-100%) during the first 3 months post-CRT. Five (26%) patients had acute hospital encounters during CRT or within 3 months of CRT completion. Two patients (11%) experienced CRT treatment interruptions. During CRT, 70/81 (86%) of surveys were flagged and 61/70 (87%) were acted upon by a nurse or physician within 4 days of the survey; during the first 3 months post-CRT, 47/85 (55%) were flagged and 28/47 (60%) were acted upon within 7 days. 92% of patients found it always easy to access the survey while 58% found the surveys too long or too frequent. None of the PROMIS domains had statistically significant changes during any time points. <h3>Conclusion</h3> Symptom self-reporting via a WBI is feasible during definitive chemoradiation with high patient satisfaction. Survey fatigue is common and may be mitigated by improving the WBI to make it more patient-centered and allowing patients to choose which symptoms to report.

Assessment of early and late symptom toxicity in a real-world cancer treatment population using the PRO-CTCAE.

e18663 Background: The FDA’s Draft Guidance for Core Patient-Reported Outcomes (PROs) in Cancer Clinical Trials, recommends assessment of disease-related symptoms, symptomatic adverse events, overall side effect impact, physical function, and role function. This guidance also recommends that core PROs be assessed more frequently within the first few treatment cycles. The NCI’s PRO Version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) is a system to evaluate symptomatic toxicity. The objective of this study is to assess the utility of frequent assessment early in treatment, using PRO-CTCAE measures for symptom monitoring. Methods: The patient cohort (n = 248) was derived from users of PROmpt®, an application for remote patient reporting and provider symptom management, employed in routine care in 30+ integrated cancer treatment centers. Patients were enrolled (9/20-10/21) at treatment initiation. Baseline characteristics were assessed by survey and review of patient EMR records. PRO-CTCAE derived surveys of 14 core symptoms (pain, shortness-of-breath, nausea, diarrhea, sadness, anxiety, constipation, fever, neuropathy, insomnia, urinary problems, decreased appetite, fatigue and mouth sores) were administered weekly. Patients who completed surveys in weeks 1 – 3 AND weeks 9 – 11 were selected for analysis (n = 75), with weekly incidences calculated for these windows. Differences were tested using dependent measures T-test. Exploratory analysis of differences by gender, frailty status, and tumor type were also performed. Results: Overall cohort was predominantly female (86.7%), with mean age 59.6 yrs. Subjects with baseline multi-dimensional geriatric assessments (MGA), were 73% fit, 24.3% intermediate and 2.7% frail. The majority of symptoms (11 of 14) showed directional decline over time, with 6 trending towards significance (p &lt; / = 0.10). Increases, however, were statistically significant for neuropathy(p = 0.01) and directional for shortness-of-breath (p = 0.10) and mouth sores (p = 0.32). Conclusions: Findings support recommendations for frequent, early assessment, with weekly surveys showing higher symptom incidence for most items compared with later assessment. Observation of late symptom increases support continued, regular monitoring for timely management of emerging symptoms with continued treatment.

Differences in clinician and patient assessment of baseline neuropathy in patients receiving taxane-based chemotherapy enrolled to SWOG S1714 (NCT# 03939481).

12024 Background: Chemotherapy induced peripheral neuropathy (CIPN) can lead to treatment dose reduction or discontinuation and significantly impact quality of life and functional status. Clinical trials have historically excluded patients with pre-existing neuropathy. Thus, it is unknown how many patients start treatment with baseline neuropathy as well as the impact on the trajectory of neuropathy symptoms. There are several patient- and clinician-based methods to assess CIPN; however, there is no consensus on the best method to evaluate CIPN or whether clinician versus patient assessment differs at baseline. Methods: In SWOG 1714, we enrolled patients ≥ 18 years of age with Stage I-III non-small cell lung, breast, or ovarian/fallopian tube/peritoneal cancer starting treatment with a taxane. Patients with baseline neuropathy were eligible. Neuropathy was assessed with patient-reported outcomes (PROs), including the European Organization for Research and Treatment of Cancer QLQ-CIPN20 (CIPN-20) and the PRO version of the Common Terminology criteria for Adverse Events (PRO-CTCAE) for severity of and interference caused by numbness and tingling, and the clinician-assessed National Cancer Institute (NCI)-CTCAE Grading Scale Version 5.0 for nervous system disorders. Results: Of 1336 patients enrolled on S1714, 1322 (99.0%) were eligible. The median age was 55.7 years (range 23.9-85.5) and 98.9% were female. The cohort was racially/ethnically diverse with 73.6% White, 11.3% Black, 4.6% Asian, and 10.5% Other and 10.5% Hispanic/Latino. Most of the patients enrolled had breast cancer (91%) and 67 patients (5.1%) reported having a neurological condition. Paclitaxel was administered to 60.2% and docetaxel to 39.8% and 98.5% planned to start treatment with full dose of taxane. Based on clinician assessment with NCI-CTCAE, 87.6% of patients at baseline had Grade 0 peripheral sensory neuropathy, 10.2% Grade 1, 2.0% Grade 2, and 0.2% Grade 3. The mean baseline CIPN-20 sensory subscore (range 0-100, higher number indicating greater severity) was 5.68 (standard deviation 10.41). Using the PRO-CTCAE for severity of numbness and tingling, 75.4% reported no baseline symptoms, 18.2% "mild", 4.8% "moderate", 1.1% "severe", and 0.5% "very severe" symptoms. With respect to interference of numbness and tingling with daily activities, 88.5% reported “not at all”, 8.3% “a little bit”, 2.0% “somewhat”, 0.9% “quite a bit”, and 0.3% “very much”. Conclusions: In this diverse cohort of predominantly breast cancer patients, there was limited evidence of significant pre-existing neuropathy. Clinician assessments of neuropathy may underestimate the symptoms of patients, emphasizing the importance of PROs in evaluating symptoms, particularly when baseline symptom is an exclusion criterion for clinical trials. Funding: NIH/NCI/NCORP grant UG1CA189974