Preoperative Treatment of Locally Advanced Rectal Cancer.

BACKGROUND: Pelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain. METHODS: We conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects. RESULTS: From June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy. CONCLUSIONS: In patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).

A randomized phase 3 trial of interferon-α vs hydroxyurea in polycythemia vera and essential thrombocythemia.

The goal of therapy for patients with essential thrombocythemia (ET) and polycythemia vera (PV) is to reduce thrombotic events by normalizing blood counts. Hydroxyurea (HU) and interferon-α (IFN-α) are the most frequently used cytoreductive options for patients with ET and PV at high risk for vascular complications. Myeloproliferative Disorders Research Consortium 112 was an investigator-initiated, phase 3 trial comparing HU to pegylated IFN-α (PEG) in treatment-naïve, high-risk patients with ET/PV. The primary endpoint was complete response (CR) rate at 12 months. A total of 168 patients were treated for a median of 81.0 weeks. CR for HU was 37% and 35% for PEG (P = .80) at 12 months. At 24 to 36 months, CR was 20% to 17% for HU and 29% to 33% for PEG. PEG led to a greater reduction in JAK2V617F at 24 months, but histopathologic responses were more frequent with HU. Thrombotic events and disease progression were infrequent in both arms, whereas grade 3/4 adverse events were more frequent with PEG (46% vs 28%). At 12 months of treatment, there was no significant difference in CR rates between HU and PEG. This study indicates that PEG and HU are both effective treatments for PV and ET. With longer treatment, PEG was more effective in normalizing blood counts and reducing driver mutation burden, whereas HU produced more histopathologic responses. Despite these differences, both agents did not differ in limiting thrombotic events and disease progression in high-risk patients with ET/PV. This trial was registered at www.clinicaltrials.gov as #NCT01259856.

At what COST?: A prospective longitudinal cohort assessment of financial toxicity, quality of life, and associated risk factors in patients with plasma cell disorders.

Financial toxicity is prevalent and harmful to patients with plasma cell disorders.

Optimization of alert notifications in electronic patient-reported outcome (ePRO) remote symptom monitoring systems (AFT-39).

PURPOSE: Clinical benefits result from electronic patient-reported outcome (ePRO) systems that enable remote symptom monitoring. Although clinically useful, real-time alert notifications for severe or worsening symptoms can overburden nurses. Thus, we aimed to algorithmically identify likely non-urgent alerts that could be suppressed. METHODS: We evaluated alerts from the PRO-TECT trial (Alliance AFT-39) in which oncology practices implemented remote symptom monitoring. Patients completed weekly at-home ePRO symptom surveys, and nurses received real-time alert notifications for severe or worsening symptoms. During parts of the trial, patients and nurses each indicated whether alerts were urgent or could wait until the next visit. We developed an algorithm for suppressing alerts based on patient assessment of urgency and model-based predictions of nurse assessment of urgency. RESULTS: 593 patients participated (median age = 64 years, 61% female, 80% white, 10% reported never using computers/tablets/smartphones). Patients completed 91% of expected weekly surveys. 34% of surveys generated an alert, and 59% of alerts prompted immediate nurse actions. Patients considered 10% of alerts urgent. Of the remaining cases, nurses considered alerts urgent more often when patients reported any worsening symptom compared to the prior week (33% of alerts with versus 26% without any worsening symptom, p = 0.009). The algorithm identified 38% of alerts as likely non-urgent that could be suppressed with acceptable discrimination (sensitivity = 80%, 95% CI [76%, 84%]; specificity = 52%, 95% CI [49%, 55%]). CONCLUSION: An algorithm can identify remote symptom monitoring alerts likely to be considered non-urgent by nurses, and may assist in fostering nurse acceptance and implementation feasibility of ePRO systems.

Recommendations on the use of item libraries for patient-reported outcome measurement in oncology trials: findings from an international, multidisciplinary working group.

The use of item libraries for patient-reported outcome (PRO) measurement in oncology allows for the customisation of PRO assessment to measure key health-related quality of life concepts of relevance to the target population and intervention. However, no high-level recommendations exist to guide users on the design and implementation of these customised PRO measures (item lists) across different PRO measurement systems. To address this issue, a working group was set up, including international stakeholders (academic, independent, industry, health technology assessment, regulatory, and patient advocacy), with the goal of creating recommendations for the use of item libraries in oncology trials. A scoping review was carried out to identify relevant publications and highlight any gaps. Stakeholders commented on the available guidance for each research question, proposed recommendations on how to address gaps in the literature, and came to an agreement using discussion-based methods. Nine primary research questions were identified that formed the scope and structure of the recommendations on how to select items and implement item lists created from item libraries. These recommendations address methods to drive item selection, plan the structure and analysis of item lists, and facilitate their use in conjunction with other measures. The findings resulted in high-level, instrument-agnostic recommendations on the use of item-library-derived item lists in oncology trials.

Phase 1/1b study of azacitidine and hedgehog pathway inhibitor sonidegib in patients with myeloid neoplasms.

BACKGROUND: Myeloid neoplasms (myelodysplastic syndrome [MDS], myelofibrosis, and chronic myelomonocytic [CMML]) are aggressive hematological malignancies for which, despite recent approvals, novel therapies are needed to improve clinical outcomes. The hedgehog (HH) pathway is one of the main pathways for cancer stem cells survival and several HH inhibitors (HHi) are approved in clinical practice. METHODS: Sonidegib (SON), an oral HHi, was tested in this phase 1/1b trial in combination with azacitidine (AZA, 75 mg/m2 days ×7) in patients with newly diagnosed and relapsed/refractory (r/r) chronic MN or acute myeloid leukemia (AML). RESULTS: Sixty-two patients (28 [45%] newly diagnosed) were treated in this study, including 10 patients in the dose-finding component and 52 patients in phase 1b. SON 200 mg oral daily on days 1-28 each cycle was deemed the recommended dose for phase 1b. Out of 21 rrAML patients, two achieved response (one complete response/one morphologic leukemia-free state) with no responses seen in seven r/r MDS/CMML patients. In newly diagnosed AML/MDS, response was seen in six (three had complete remission, two had morphological leukemia-free status) of 27 patients. Median overall survival was 26.4 and 4.7 months for newly diagnosed MDS and AML, respectively. Safety was satisfactory with common (>20%) side effects including fatigue, constipation, nausea, cough, insomnia, and diarrhea. Only 7% of patients died in the study, and none of the deaths were deemed related to treatment. CONCLUSIONS: Our study shows that AZA + SON are a safe combination in a patient with MN. Similar to other hedgehog inhibitors, this combination yielded limited response rate in patients with myeloid neoplasms.

Patient-reported Adverse Events During Neoadjuvant Therapy in a Phase 2 Borderline Resectable Pancreatic Cancer Clinical Trial (Alliance A021501).

OBJECTIVE: We sought to evaluate symptomatic adverse event (AE) rates among patients with pancreatic cancer receiving neoadjuvant therapy on clinical trial (A021501) using the Patient-Reported Outcomes Common Terminology Criteria for Adverse Events (PRO-CTCAE). BACKGROUND: To date, pancreatic cancer clinical trials have measured AEs using standard physician reporting [Common Terminology Criteria for Adverse Events (CTCAE)]. Patient-reported symptomatic AEs have been incompletely characterized. METHODS: A021501 (December 31, 2016-January 1, 2019) randomized patients with borderline resectable pancreatic ductal adenocarcinoma to 8 doses of mFOLFIRINOX (Arm 1) or 7 doses of mFOLFIRINOX+hypofractionated radiotherapy (Arm 2), followed by pancreatectomy and adjuvant FOLFOX6. Patients completed PRO-CTCAE assessments at baseline, on day 1 of each chemotherapy cycle, and daily during radiotherapy. RESULTS: Of 126 patients, 96 (76%) initiated treatment and completed a baseline plus at least 1 postbaseline PRO-CTCAE assessment. Diarrhea and fatigue were the only symptomatic grade 3 or higher AEs identified in at least 10% of patients using CTCAE. At least 10% of all patients reported an adjusted PRO-CTCAE composite grade 3 AE during neoadjuvant treatment for 10 of 15 items: anxiety (10%), bloating of abdomen (16%), decreased appetite (18%), diarrhea (13%), dry mouth (21%), fatigue (36%), nausea (18%), generalized pain (16%), abdominal pain (21%), and problems tasting (32%). Decreased appetite was higher in Arm 2 than in Arm 1 ( P =0.0497); no other differences between study arms were observed. CONCLUSION: Symptomatic AEs during neoadjuvant therapy were common and were reported more frequently by patients using PRO-CTCAE than were recorded by clinicians using standard CTCAE.

Identifying meaningful change on PROMIS short forms in cancer patients: a comparison of item response theory and classic test theory frameworks.

BACKGROUND: This study compares classical test theory and item response theory frameworks to determine reliable change. Reliable change followed by anchoring to the change in categorically distinct responses on a criterion measure is a useful method to detect meaningful change on a target measure. METHODS: Adult cancer patients were recruited from five cancer centers. Baseline and follow-up assessments at 6 weeks were administered. We investigated short forms derived from PROMIS® item banks on anxiety, depression, fatigue, pain intensity, pain interference, and sleep disturbance. We detected reliable change using reliable change index (RCI). We derived the T-scores corresponding to the RCI calculated under IRT and CTT frameworks using PROMIS® short forms. For changes that were reliable, meaningful change was identified using patient-reported change in PRO-CTCAE by at least one level. For both CTT and IRT approaches, we applied one-sided tests to detect reliable improvement or worsening using RCI. We compared the percentages of patients with reliable change and reliable/meaningful change. RESULTS: The amount of change in T score corresponding to RCICTT of 1.65 ranged from 5.1 to 9.2 depending on domains. The amount of change corresponding to RCIIRT of 1.65 varied across the score range, and the minimum change ranged from 3.0 to 8.2 depending on domains. Across domains, the RCICTT and RCIIRT classified 80% to 98% of the patients consistently. When there was disagreement, the RCIIRT tended to identify more patients as having reliably changed compared to RCICTT if scores at both timepoints were in the range of 43 to 78 in anxiety, 45 to 70 in depression, 38 to 80 in fatigue, 35 to 78 in sleep disturbance, and 48 to 74 in pain interference, due to smaller standard errors in these ranges using the IRT method. The CTT method found more changes compared to IRT for the pain intensity domain that was shorter in length. Using RCICTT, 22% to 66% had reliable change in either direction depending on domains, and among these patients, 62% to 83% had meaningful change. Using RCIIRT, 37% to 68% had reliable change in either direction, and among these patients, 62% to 81% had meaningful change. CONCLUSION: Applying the two-step criteria demonstrated in this study, we determined how much change is needed to declare reliable change at different levels of baseline scores. We offer reference values for percentage of patients who meaningfully change for investigators using the PROMIS instruments in oncology.

Lessons learned from conducting the first cancer care delivery trial in the Alliance for Clinical Trials in Oncology (Alliance A191402CD).

INTRODUCTION: Testing healthcare delivery interventions in rigorous clinical trials is a critical step in improving patient care, but conducting multisite randomized clinical trials to test the effect of care delivery interventions has unique challenges and requires foresight and planning. METHODS: We conducted the first care delivery trial (A191402CD) in the Alliance for Clinical Trials in Oncology, a National Cancer Institute Community Oncology Research Program research base, which tested the effectiveness of two different decision aids for supporting shared decision-making about prostate cancer treatment. Our experience illustrates the kind of challenges that confront care delivery researchers as they seek to test interventions to improve the experiences of patients. RESULTS: Lessons learned include the following: cluster-randomized designs introduce complexity; workflow disruption can discourage site participation; evidence-based methods may not always be sufficient. CONCLUSION: We conclude with the following recommendations: assessing feasibility requires special rigor; relationships and interpersonal dynamics must be leveraged. Our experiences may inform future care delivery research.

Decision aids for localized prostate cancer in diverse minority men: Primary outcome results from a multicenter cancer care delivery trial (Alliance A191402CD).

BACKGROUND: Decision aids (DAs) can improve knowledge for prostate cancer treatment. However, the relative effects of DAs delivered within the clinical encounter and in more diverse patient populations are unknown. A multicenter cluster randomized controlled trial with a 2×2 factorial design was performed to test the effectiveness of within-visit and previsit DAs for localized prostate cancer, and minority men were oversampled. METHODS: The interventions were delivered in urology practices affiliated with the NCI Community Oncology Research Program Alliance Research Base. The primary outcome was prostate cancer knowledge (percent correct on a 12-item measure) assessed immediately after a urology consultation. RESULTS: Four sites administered the previsit DA (39 patients), 4 sites administered the within-visit DA (44 patients), 3 sites administered both previsit and within-visit DAs (25 patients), and 4 sites provided usual care (50 patients). The median percent correct in prostate cancer knowledge, based on the postvisit knowledge assessment after the intervention delivery, was as follows: 75% for the pre+within-visit DA study arm, 67% for the previsit DA only arm, 58% for the within-visit DA only arm, and 58% for the usual-care arm. Neither the previsit DA nor the within-visit DA had a significant impact on patient knowledge of prostate cancer treatments at the prespecified 2.5% significance level (P = .132 and P = .977, respectively). CONCLUSIONS: DAs for localized prostate cancer treatment provided at 2 different points in the care continuum in a trial that oversampled minority men did not confer measurable gains in prostate cancer knowledge.

Randomized Phase II Study of Two Doses of Pixantrone in Patients with Metastatic Breast Cancer (NCCTG N1031, Alliance).

BACKGROUND: Anthracycline use in metastatic breast cancer (MBC) is hindered by cumulative exposure limits and risk of cardiotoxicity. Pixantrone, a novel aza-anthracenedione with structural similarities to mitoxantrone and anthracyclines, is theorized to exhibit less cardiotoxicity, mainly due to lack of iron binding. We conducted a randomized phase II study to evaluate the efficacy and safety of 2 dosing schedules of pixantrone in patients with refractory HER2-negative MBC. METHODS: Intravenous pixantrone was administered at 180 mg/m2 every 3 weeks (group A) versus 85 mg/m2 on days 1, 8, and 15 of a 28-day cycle (group B). Primary endpoint was objective response rate (ORR) and secondary endpoints included progression-free survival (PFS), median 6-month PFS, overall survival (OS), safety, quality of life, and serial assessment of circulating tumor cells. A 20% ORR was targeted as sufficient for further testing of pixantrone in this patient population. RESULTS: Forty-five patients were evaluable, with 2 confirmed partial responses in group A and 1 in group B. The trial was terminated due to insufficient activity. Overall median PFS and OS were 2.8 (95% confidence interval [CI]: 2.0-4.1) and 16.8 (95% CI: 8.9-21.6) months, respectively. Notable overall grade 3-4 adverse events were the following: neutrophil count decrease (62%), fatigue (16%), and decrease in ejection fraction (EF) (4%). CONCLUSION: Pixantrone has insufficient activity in the second- and third-line MBC setting. It appears, however, to have limited cardiotoxicity. (ClinicalTrials.gov ID: NCT01086605).

An Exploratory Analysis of the "Was It Worth It?" Questionnaire as a Novel Metric to Capture Patient Perceptions of Cancer Treatment.

OBJECTIVES: Asking "Was it worth it?" (WIWI) potentially captures the patient perception of a treatment's benefit weighed against its harms. This exploratory analysis evaluates the WIWI questionnaire as a metric of patients' perspectives on the worthwhileness of cancer treatment. METHODS: A 3-item WIWI questionnaire was assessed at end of treatment in patients with cancer on the COMET-2 trial (NCT01522443). WIWI items were evaluated to determine their association with quality of life (QOL), treatment duration, end-of-treatment reason, patient-reported adverse events (AEs), and disease response. RESULTS: A total of 65 patients completed the questionnaire; 40 (62%), 16 (25%), and 9 (14%) patients replied yes, uncertain, and no to "Was it worthwhile for you to receive the cancer treatment given in this study?" (item 1), respectively; 39 (60%), 12 (18%), and 14 (22%) to "If you had to do it over again, would you choose to have this cancer treatment?"; and 40 (62%), 14 (22%), and 11 (17%) to "Would you recommend this cancer treatment to others?" Patients responding yes to item 1 remained on treatment longer than those responding uncertain or no (mean 23.0 vs 11.3 weeks, P<.001). Patients responding uncertain/no to item 1 discontinued treatment because of AEs more frequently than those responding yes (36% vs 7.5%, P=.004) and demonstrated meaningful decline in QOL from baseline (-2.5 vs -0.2 mean change, P<.001). Associations between WIWI responses and most patient-reported AEs or treatment efficacy did not reach statistical significance. CONCLUSIONS: Patients who responded affirmatively on WIWI items remained on therapy longer, were less likely to stop treatment because of AEs, and demonstrated superior QOL. The WIWI may inform clinical practice, oncology research, and value frameworks.

Missing data strategies for the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) in Alliance A091105 and COMET-2.

PURPOSE: Missing scores complicate analysis of the Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) because patients with and without missing scores may systematically differ. We focus on optimal analysis methods for incomplete PRO-CTCAE items, with application to two randomized, double-blind, placebo-controlled, phase III trials. METHODS: In Alliance A091105 and COMET-2, patients completed PRO-CTCAE items before randomization and several times post-randomization (N = 64 and 107, respectively). For each trial, we conducted between-arm comparisons on the PRO-CTCAE via complete-case two-sample t-tests, mixed modeling with contrast, and multiple imputation followed by two-sample t-tests. Because interest lies in whether CTCAE grades can inform missing PRO-CTCAE scores, we performed multiple imputation with and without CTCAE grades as auxiliary variables to assess the added benefit of including them in the imputation model relative to only including PRO-CTCAE scores across all cycles. RESULTS: PRO-CTCAE completion rates ranged from 100.0 to 71.4% and 100.0 to 77.1% across time in A091105 and COMET-2, respectively. In both trials, mixed modeling and multiple imputation provided the most similar estimates of the average treatment effects. Including CTCAE grades in the imputation model did not consistently narrow confidence intervals of the average treatment effects because correlations for the same PRO-CTCAE item between different cycles were generally stronger than correlations between each PRO-CTCAE item and its corresponding CTCAE grade at the same cycle. CONCLUSION: For between-arm comparisons, mixed modeling and multiple imputation are informative techniques for handling missing PRO-CTCAE scores. CTCAE grades do not provide added benefit for informing missing PRO-CTCAE scores. CLINICALTRIALS: gov Identifiers: NCT02066181 (Alliance A091105); NCT01522443 (COMET-2).

Effects of patient-reported outcome assessment order.

BACKGROUND: In clinical trials and clinical practice, patient-reported outcomes are almost always assessed using multiple patient-reported outcome measures at the same time. This raises concerns about whether patient responses are affected by the order in which the patient-reported outcome measures are administered. METHODS: This questionnaire-based study of order effects included adult cancer patients from five cancer centers. Patients were randomly assigned to complete questionnaires via paper booklets, interactive voice response system, or tablet web survey. Linear Analogue Self-Assessment, Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events, and Patient-Reported Outcomes Measurement Information System assessment tools were each used to measure general health, physical function, social function, emotional distress/anxiety, emotional distress/depression, fatigue, sleep, and pain. The order in which the three tools, and domains within tools, were presented to patients was randomized. Rates of missing data, scale scores, and Cronbach's alpha coefficients were compared by the order in which they were assessed. Analyses included Cochran-Armitage trend tests and mixed models adjusted for performance score, age, sex, cancer type, and curative intent. RESULTS: A total of 1830 patients provided baseline patient-reported outcome assessments. There were no significant trends in rates of missing values by whether a scale was assessed earlier or later. The largest order effect for scale scores was due to a large mean score at one assessment time point. The largest difference in Cronbach's alpha between the versions for the Patient-Reported Outcomes Measurement Information System scales was 0.106. CONCLUSION: The well-being of a cancer patient has many different aspects such as pain, fatigue, depression, and anxiety. These are assessed using a variety of surveys often collected at the same time. This study shows that the order in which the different aspects are collected from the patient is not important.

Effect of Electronic Symptom Monitoring on Patient-Reported Outcomes Among Patients With Metastatic Cancer: A Randomized Clinical Trial.

Importance: Electronic systems that facilitate patient-reported outcome (PRO) surveys for patients with cancer may detect symptoms early and prompt clinicians to intervene. Objective: To evaluate whether electronic symptom monitoring during cancer treatment confers benefits on quality-of-life outcomes. Design, Setting, and Participants: Report of secondary outcomes from the PRO-TECT (Alliance AFT-39) cluster randomized trial in 52 US community oncology practices randomized to electronic symptom monitoring with PRO surveys or usual care. Between October 2017 and March 2020, 1191 adults being treated for metastatic cancer were enrolled, with last follow-up on May 17, 2021. Interventions: In the PRO group, participants (n = 593) were asked to complete weekly surveys via an internet-based or automated telephone system for up to 1 year. Severe or worsening symptoms triggered care team alerts. The control group (n = 598) received usual care. Main Outcomes and Measures: The 3 prespecified secondary outcomes were physical function, symptom control, and health-related quality of life (HRQOL) at 3 months, measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (QLQ-C30; range, 0-100 points; minimum clinically important difference [MCID], 2-7 for physical function; no MCID defined for symptom control or HRQOL). Results on the primary outcome, overall survival, are not yet available. Results: Among 52 practices, 1191 patients were included (mean age, 62.2 years; 694 [58.3%] women); 1066 (89.5%) completed 3-month follow-up. Compared with usual care, mean changes on the QLQ-C30 from baseline to 3 months were significantly improved in the PRO group for physical function (PRO, from 74.27 to 75.81 points; control, from 73.54 to 72.61 points; mean difference, 2.47 [95% CI, 0.41-4.53]; P = .02), symptom control (PRO, from 77.67 to 80.03 points; control, from 76.75 to 76.55 points; mean difference, 2.56 [95% CI, 0.95-4.17]; P = .002), and HRQOL (PRO, from 78.11 to 80.03 points; control, from 77.00 to 76.50 points; mean difference, 2.43 [95% CI, 0.90-3.96]; P = .002). Patients in the PRO group had significantly greater odds of experiencing clinically meaningful benefits vs usual care for physical function (7.7% more with improvements of ≥5 points and 6.1% fewer with worsening of ≥5 points; odds ratio [OR], 1.35 [95% CI, 1.08-1.70]; P = .009), symptom control (8.6% and 7.5%, respectively; OR, 1.50 [95% CI, 1.15-1.95]; P = .003), and HRQOL (8.5% and 4.9%, respectively; OR, 1.41 [95% CI, 1.10-1.81]; P = .006). Conclusions and Relevance: In this report of secondary outcomes from a randomized clinical trial of adults receiving cancer treatment, use of weekly electronic PRO surveys to monitor symptoms, compared with usual care, resulted in statistically significant improvements in physical function, symptom control, and HRQOL at 3 months, with mean improvements of approximately 2.5 points on a 0- to 100-point scale. These findings should be interpreted provisionally pending results of the primary outcome of overall survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03249090.

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.

Expanding Beyond Maximum Grade: Chemotherapy Toxicity over Time by Age and Performance Status in Advanced Non-Small Cell Lung Cancer in CALGB 9730 (Alliance A151729).

BACKGROUND: Prior comparisons of chemotherapy adverse events (AEs) by age and performance status (PS) are limited by the traditional maximum grade approach, which ignores low-grade AEs and longitudinal changes. MATERIALS AND METHODS: To compare fatigue and neuropathy longitudinally by age (<65, ≥65 years) and PS (0-1, 2), we analyzed data from a large phase III trial of carboplatin and paclitaxel versus paclitaxel for advanced non-small cell lung cancer (CALGB 9730, n = 529). We performed multivariable (a) linear mixed models to estimate mean AE grade over time, (b) linear regression to estimate area under the curve (AUC), and (c) proportional hazards models to estimate the hazard ratio of developing grade ≥2 AE, as well as traditional maximum grade analyses. RESULTS: Older patients had on average a 0.17-point (95% confidence interval [CI], 0.00-0.34; p = .049) higher mean fatigue grade longitudinally compared with younger patients. PS 2 was associated with earlier development of grade ≥2 fatigue (hazard ratio [HR], 1.56; 95% CI, 1.07-2.27; p = .02). For neuropathy, older age was associated with earlier development of grade ≥2 neuropathy (HR, 1.41; 95% CI, 1.00-1.97; p = .049). Patients with PS 2 had a 1.30 point lower neuropathy AUC (95% CI, -2.36 to -0.25; p = .02) compared with PS 0-1. In contrast, maximum grade analyses only detected a higher percentage of older adults with grade ≥3 fatigue and neuropathy at some point during treatment. CONCLUSION: Our comparison of complementary but distinct aspects of chemotherapy toxicity identified important longitudinal differences in fatigue and neuropathy by age and PS that are missed by the traditional maximum grade approach. Clinical trial identification number: NCT00003117 (CALGB 9730) IMPLICATIONS FOR PRACTICE: The traditional maximum grade approach ignores persistent low-grade adverse events (AEs) and changes over time. This toxicity over time analysis of fatigue and neuropathy during chemotherapy for advanced non-small cell lung cancer demonstrates how to use longitudinal methods to comprehensively characterize AEs over time by age and performance status (PS). We identified important longitudinal differences in fatigue and neuropathy that are missed by the maximum grade approach. This new information about how older adults and patients with PS 2 experience these toxicities longitudinally may be used clinically to improve discussions about treatment options and what to expect to inform shared decision making and symptom management.

Sorafenib for Advanced and Refractory Desmoid Tumors.

BACKGROUND: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care. METHODS: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated. RESULTS: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). CONCLUSIONS: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).

Randomized Phase II Trial of Capecitabine and Lapatinib with or without IMC-A12 (Cituxumumab) in Patients with HER2-Positive Advanced Breast Cancer Previously Treated with Trastuzumab and Chemotherapy: NCCTG N0733 (Alliance).

PURPOSE: To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. PATIENTS AND METHODS: Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥ 3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome. RESULTS: From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52-1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥ 3 adverse events, overall QOL change from baseline after 4 cycles of treatment. CONCLUSION: The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC. CLINICAL TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT00684983.

Tolerability and toxicity of trastuzumab or trastuzumab + lapatinib in older patients: a sub-analysis of the ALTTO trial (BIG 2-06; NCCTG (Alliance) N063D).

PURPOSE: Little is known about the use of trastuzumab or trastuzumab + lapatinib in older patients. We have performed a sub-analysis of the Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation (ALTTO) trial focused on toxicity and treatment completion of both regimens in older patients (≥ 65 years old) METHODS: The ALTTO trial randomised 8381 patients with early HER2-positive BC in 4 arms. Eligible patients for this study were those having received at least one dose of assigned treatment in either the trastuzumab or trastuzumab + lapatinib arms. Treatment completion was evaluated through the rate of temporary treatment interruptions, permanent treatment discontinuations and lapatinib dose reductions. Toxicity was evaluated via a selected subset of adverse events of interest (AEI). Risk factors for both treatment completion outcomes and toxicity were investigated, including comorbidities and use of 5 or more co-medications at randomization. RESULTS: A total of 430 patients ≥ 65 year were eligible. Median age was 68 (range 65-80). In comparison with the younger cohort, older patients had a significantly higher number of comorbidities at randomization (p < 0.001). Treatment completion outcomes were worse, particularly in the trastuzumab + lapatinib arm. Adverse events of interest were likewise more common in the trastuzumab + lapatinib arm with higher AEI rates (63.4% in younger vs 78.0% in older, p < 0.001). Concomitant chemotherapy was associated with worse treatment completion outcomes among older patients. CONCLUSION: Trastuzumab plus lapatinib was significantly more toxic among older patients and had worse treatment completion. Trastuzumab was generally well tolerated.