Randomized study of induction with bendamustine-rituximab ± bortezomib and maintenance with rituximab ± lenalidomide for MCL.

ABSTRACT: Although initial therapy of mantle cell lymphoma (MCL) is not standardized, bendamustine plus rituximab (BR) is commonly used in older patients. Rituximab (R) maintenance after induction is often used. Thus, the open-label, randomized phase 2 ECOG-ACRIN Cancer Research Group E1411 trial was designed to test 2 questions: (1) does addition of bortezomib to BR induction (BVR) and/or (2) addition of lenalidomide to rituximab (LR) maintenance improve progression-free survival (PFS) in patients with treatment-naïve MCL? From 2012 to 2016, 373 previously untreated patients, 87% aged ≥60 years, were enrolled in this trial. At a median follow-up of 7.5 years, there is no difference in the median PFS of BR compared with BVR (5.5 vs 6.4 years; hazard ratio [HR], 0.90; 90% confidence interval [CI], 0.70-1.16). There were no unexpected additional toxicities with BVR treatment compared with BR, with no impact on total dose/duration of treatment received. Independent of the induction treatment, addition of lenalidomide did not significantly improve PFS, with median PFS in R vs LR (5.9 vs 7.2 years; HR, 0.84; 90% CI, 0.62-1.15). Most patients completed the planned 24 cycles of LR at the scheduled dose. In summary, adding bortezomib to BR induction does not prolong PFS in treatment-naïve MCL, and LR maintenance was not associated with longer PFS compared with R alone after BR. Nonetheless, the >5-year median PFS outcomes in this prospective cooperative group trial indicate the efficacy of BR followed by R maintenance as highly effective initial therapy for older patients with MCL. This trial was registered at www.clinicaltrials.gov as #NCT01415752.

The effect of neighborhood socioeconomic disadvantage on smoking status, quit attempts, and receipt of cessation support among adults with cancer: Results from nine ECOG-ACRIN Cancer Research Group trials.

BACKGROUND: Tobacco use is associated with adverse outcomes among patients diagnosed with cancer. Socioeconomic determinants influence access and utilization of tobacco treatment; little is known about the relationship between neighborhood socioeconomic disadvantage (NSD) and tobacco assessment, assistance, and cessation among patients diagnosed with cancer. METHODS: A modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) was administered to patients enrolled in nine ECOG-ACRIN clinical trials. We examined associations of NSD with (1) smoking status, (2) receiving tobacco cessation assessment and support, and (3) cessation behaviors. NSD was classified by tertiles of the Area Deprivation Index. Associations between NSD and tobacco variables were evaluated using logistic regression. RESULTS: A total of 740 patients completing the C-TUQ were 70% male, 94% White, 3% Hispanic, mean age 58.8 years. Cancer diagnoses included leukemia 263 (36%), lymphoma 141 (19%), prostate 131 (18%), breast 79 (11%), melanoma 69 (9%), myeloma 53 (7%), and head and neck 4 (0.5%). A total of 402 (54%) never smoked, 257 (35%) had formerly smoked, and 81 (11%) were currently smoking. Patients in high disadvantaged neighborhoods were approximately four times more likely to report current smoking (odds ratio [OR], 3.57; 95% CI, 1.69-7.54; p = .0009), and more likely to report being asked about smoking (OR, 4.24; 95% CI, 1.64-10.98; p = .0029), but less likely to report receiving counseling (OR, 0.11; 95% CI, 0.02-0.58; p = .0086) versus those in the least disadvantaged neighborhoods. CONCLUSIONS: Greater neighborhood socioeconomic disadvantage was associated with smoking but less cessation support. Increased cessation support in cancer care is needed, particularly for patients from disadvantaged neighborhoods.

Adjuvant platinum versus capecitabine for residual, invasive, triple-negative breast cancer: Patient-reported outcomes in ECOG-ACRIN EA1131.

BACKGROUND: Patient-reported outcomes (PROs) are a better tool for evaluating the experiences of patients who have symptomatic, treatment-associated adverse events (AEs) compared with clinician-rated AEs. The authors present PROs assessing health-related quality of life (HRQoL) and treatment-related neurotoxicity for adjuvant capecitabine versus platinum on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) EA1131 trial (ClinicalTrials.gov identifier NCT02445391). METHODS: Participants completed the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index (NFBSI-16) and the Functional Assessment of Cancer Therapy-Gynecologic Oncology Group neurotoxicity subscale (platinum arm only) at baseline, cycle 3 day 1 (C3D1), 6 months, and 15 months. Because of early termination, power was insufficient to test the hypothesis that HRQoL, as assessed by the NFBSI-16 treatment side-effect (TSE) subscale, would be better at 6 and 15 months in the capecitabine arm; all analyses were exploratory. Means were compared by using t-tests or the Wilcoxon rank-sum test, and proportions were compared by using the χ2 test. RESULTS: Two hundred ninety-six of 330 eligible patients provided PROs. The mean NFBSI-16 TSE subscale score was lower for the platinum arm at baseline (p = .02; absolute difference, 0.6 points) and for the capecitabine arm at C3D1 (p = .04; absolute difference, 0.5 points), but it did not differ at other times. The mean change in TSE subscale scores differed between the arms from baseline to C3D1 (platinum arm, 0.15; capecitabine arm, -0.72; p = .03), but not from baseline to later time points. The mean decline in Functional Assessment of Cancer Therapy-Gynecologic Oncology Group neurotoxicity subscale scores exceeded the minimal meaningful change (1.38 points) from baseline to each subsequent time point (all p < .05). CONCLUSIONS: Despite the similar frequency of clinician-rated AEs, PROs identified greater on-treatment symptom burden with capecitabine and complemented clinician-rated AEs by characterizing patients' experiences during chemotherapy.

Physicians' Hierarchy of Tumor Biomarkers for Optimizing Chemotherapy in Breast Cancer Care.

BACKGROUND: Tumor biomarkers are regularly used to guide breast cancer treatment and clinical trial enrollment. However, there remains a lack of knowledge regarding physicians' perspectives towards biomarkers and their role in treatment optimization, where treatment intensity is reduced to minimize toxicity. METHODS: Thirty-nine academic and community oncologists participated in semi-structured qualitative interviews, providing perspectives on optimization approaches to chemotherapy treatment. Interviews were audio-recorded, transcribed, and analyzed by 2 independent coders utilizing a constant comparative method in NVivo. Major themes and exemplary quotes were extracted. A framework outlining physicians' conception of biomarkers, and their comfortability with their use in treatment optimization, was developed. RESULTS: In the hierarchal model of biomarkers, level 1 is comprised of standard-of-care (SoC) biomarkers, defined by a strong level of evidence, alignment with national guidelines, and widespread utilization. Level 2 includes SoC biomarkers used in alternative contexts, in which physicians expressed confidence, yet less certainty, due to a lack of data in certain subgroups. Level 3, or experimental, biomarkers created the most diverse concerns related to quality and quantity of evidence, with several additional modulators. CONCLUSION: This study demonstrates that physicians conceptualize the use of biomarkers for treatment optimization in successive levels. This hierarchy can be used to guide trialists in the development of novel biomarkers and design of future trials.

A randomized phase III double-blind placebo-controlled trial of first-line chemotherapy and trastuzumab with or without bevacizumab for patients with HER2/neu-positive metastatic breast cancer: a trial of the ECOG-ACRIN Cancer Research Group (E1105).

BACKGROUND: In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the pre-clinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. FINDINGS: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43-1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61-1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. CONCLUSIONS: In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time. CLINICAL TRIAL INFORMATION: NCT00520975.

Development and psychometric properties of the Functional Assessment of Cancer Therapy-Cutaneous T-Cell Lymphoma (FACT-CTCL).

BACKGROUND: Patients with Mycosis Fungoides (MF)/Sézary Syndrome (SS) can experience impacted health-related quality of life (HRQoL). OBJECTIVES: To validate the CTCL-S, a novel subscale of the Functional Assessment of Cancer Therapy - General (FACT-G), in patients with MF/SS. METHODS: Qualitative interviews were conducted with expert clinicians and MF/SS patients. Thematic analysis identified the most common concerns, and 19 items were selected.MF/SS patients were recruited from a single center. FACT-G, CTCL-S (collectively "FACT-CTCL"), Skindex29, and Visual Analogue Scale-Pruritis (VAS itch) were administered. A subset repeated FACT-CTCL and VAS itch after ≈2 weeks. Patient demographics and clinical characteristics were obtained via review of the electronic medical record.Psychometric properties were assessed. Internal consistency was estimated using Cronbach's alpha (α). Convergent and discriminant validity were assessed by comparing CTCL-S to disease stage, age, VAS itch, FACT-G, and SkinDex29. Exploratory factor analysis (EFA) was used to preliminarily assess CTCL-S dimensionality. Test-retest repeatability was summarized using intraclass correlation coefficient (ICC), within-subject standard deviation (wSD), and within-subject coefficient of variation. RESULTS: Seventy-two patients completed the initial survey, and 35 repeated the FACT-CTCL and VAS itch after ≈2 weeks. Two-thirds were male, most were white (78%). The majority (85%) had MF, 15% SS, and 75% early (stage IA-IIA) and 25% advanced (≥ stage IIB) disease. Preliminary EFA found a single predominant factor, supporting a hypothesis of unidimensionality of the CTCL-S. Internal consistency of the CTCL-S was high (α: 0.95 [95% CI: 0.93-0.96]). There was no significant change in CTCL-S average test-retest scores (ICC of 0.93 (p = 0.63)). CTCL-S was significantly lower in advanced vs early stage disease (median[IQR]: 34[26, 48] vs. 59[44, 68], p < 0.001) and strongly correlated with VAS itch (Spearman's r (rs): -0.70, 95% CI: -0.81, -0.55), FACT-G (rs: 0.77, 95% CI: 0.65, 0.85), and Skindex29 (rs: -0.90, 95% CI: -0.94, -0.84), supporting convergent validity. CTCL-S scores had little correlation with age (rs: 0.19, 95% CI: -0.05, 0.41, p = 0.12), supporting discriminant validity. CONCLUSIONS: The FACT-CTCL is a disease specific instrument for assessing HRQoL with high reproducibility and good performance in a cohort of patients with MF/SS.

The impact of non- and anthracycline-based chemotherapy on fatigue in breast cancer survivors: results from WF-97415.

PURPOSE: To examine the differential effect of non- and anthracycline-based chemotherapy on fatigue over 12 months post-diagnosis among breast cancer survivors. METHODS: This study is based on a prospective Wake Forest NCI Community Oncology Research Program (NCORP) multicenter cohort study (WF-97415) of women with stage I to III breast cancer and non-cancer controls. Analyses compared those: 1) receiving, or 2) not receiving anthracycline chemotherapy, 3) receiving aromatase inhibitors (AIs) without chemotherapy, with 4) a comparator group without a history of cancer. In-person clinic assessments were conducted at: baseline (prior to chemotherapy or start of AI therapy), and 3 and 12 months after baseline. The Functional Assessment of Chronic Illness Therapy-Fatigue scale was the primary outcome. Estimated least squares means by group using mixed models with a random subject effect, fixed effects of time and group, and the interaction between time and group was used to compare groups across time, controlling for age, comorbidities, and treatment variables. RESULTS: Among 284 women (mean age = 53.4 years, sd 11.9 years), there was a significant (p < 0.0001) group by time interaction, with a sharp increase in fatigue at 3 months in the two chemotherapy groups in comparison to the non-chemotherapy and non-cancer controls. The two chemotherapy groups did not significantly differ in fatigue at any time point. CONCLUSION: Women with breast cancer who receive non- or anthracycline-based chemotherapy experience similar trends in and levels of fatigue within the first year of treatment and greater fatigue than women receiving AIs alone or women without breast cancer.

An exploration into the relationship between insomnia and repetitive negative thinking among cancer survivors.

OBJECTIVE: Insomnia and repetitive negative thinking (RNT) are both prevalent among cancer survivors, yet little work has investigated their interrelationship. To explore the hypothesis that RNT and insomnia are related, we conducted secondary analyses on data from a pilot clinical trial of cognitive behavioral therapy for insomnia (CBT-I) for cancer survivors. METHODS: This study analyzed survey data from 40 cancer survivors with insomnia who participated in a pilot randomized trial of CBT-I. Correlations and linear regression models were used to determine associations between aspects of RNT and related constructs (fear of cancer recurrence [FCR], cancer-specific rumination, worry, and intolerance of uncertainty) and sleep (insomnia and sleep quality), while accounting for psychiatric symptoms such as anxiety and depression. Treatment-related change in RNT was examined using a series of linear mixed models. RESULTS: Evidence for an association between RNT and insomnia among cancer survivors emerged. Higher levels of FCR and cancer-related rumination were correlated with more severe insomnia symptoms and worse sleep quality. Notably, FCR levels predicted insomnia, even after controlling for anxiety and depression. Results identified potential benefits and limitations of CBT-I in addressing RNT that should be examined more thoroughly in future research. CONCLUSIONS: RNT is a potential target to consider in insomnia treatment for cancer survivors.

Fear of recurrence, emotional well-being and quality of life among long-term advanced ovarian cancer survivors.

OBJECTIVE: Although advanced stage epithelial ovarian cancer is widely considered life-threatening, 17% of women with advanced disease will survive long-term. Little is known about the health-related quality of life (QOL) of long-term ovarian cancer survivors, or how fear of recurrence might affect QOL. METHODS: 58 long-term survivors with advanced disease participated in the study. Participants completed standardized questionnaires to capture cancer history, QOL, and fear of recurrent disease (FOR). Statistical analyses included multivariable linear models. RESULTS: Participants averaged 52.8 years at diagnosis and had survived >8 years (mean:13.5); 64% had recurrent disease. Mean FACT-G, FACT-O, and FACT-O-TOI (TOI) scores were 90.7 (SD:11.6), 128.6 (SD:14.8), and 85.9 (SD:10.2) respectively. Compared to the U.S. population using T-scores, QOL for participants exceeded that of healthy adults (T-score (FACT-G) = 55.9). Overall QOL was lower in women with recurrent vs. non-recurrent disease though differences did not reach statistical significance (FACT-O = 126.1 vs. 133.3, p = 0.082). Despite good QOL, high FOR was reported in 27%. FOR was inversely associated with emotional well-being (EWB) (p < 0.001), but not associated with other QOL subdomains. In multivariable analysis, FOR was a significant predictor of EWB after adjusting for QOL (TOI). A significant interaction was observed between recurrence and FOR (p = 0.034), supporting a larger impact of FOR in recurrent disease. CONCLUSION: QOL in long-term ovarian cancer survivors was better than the average for healthy U.S. women. Despite good QOL, high FOR contributed significantly to increased emotional distress, most notably for those with recurrence. Attention to FOR may be warranted in this survivor population.

Cardiovascular Implications of Vascular Endothelial Growth Factor Inhibition Among Adolescents/Young Adults in ECOG-ACRIN E2805.

BACKGROUND: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality among adolescents and young adults (AYAs) diagnosed with cancer. The aim of this study was to assess the incidence and predictors of left ventricular systolic dysfunction (LVSD) and hypertension among AYAs receiving VEGF inhibition compared with non-AYAs. METHODS: This retrospective analysis used data from the ASSURE trial (ClinicalTrials.gov identifier: NCT00326898), in which participants with nonmetastatic, high-risk, renal cell cancer were randomized to sunitinib, sorafenib, or placebo. The incidence of LVSD (left ventricular ejection fraction decrease >15%) and hypertension (blood pressure ≥140/90 mm Hg) were compared using nonparametric tests. Multivariable logistic regression examined the association between AYA status, LVSD, and hypertension while adjusting for clinical factors. RESULTS: AYAs represented 7% (103/1,572) of the population. Over a study treatment period of 54 weeks, the incidence of LVSD was not significantly different among AYAs (3%; 95% CI, 0.6%-8.3%) versus non-AYAs (2%; 95% CI, 1.2%-2.7%). The incidence of hypertension was significantly lower among AYAs (18%; 95% CI, 7.5%-33.5%) compared with non-AYAs (46%; 95% CI, 41.9%-50.4%) in the placebo arm. In the sunitinib and sorafenib groups, the incidence of hypertension for AYAs compared with non-AYAs was 29% (95% CI, 15.1%-47.5%) versus 47% (95% CI, 42.3%-51.7%), and 54% (95% CI, 33.9%-72.5%) versus 63% (95% CI, 58.6%-67.7%), respectively. AYA status (odds ratio, 0.48; 95% CI, 0.31-0.75) and female sex (odds ratio, 0.74; 95% CI, 0.59-0.92) were each associated with a lower risk of hypertension. CONCLUSIONS: LVSD and hypertension were prevalent among AYAs. CVD among AYAs is only partially explained by cancer therapy. Understanding CVD risk among AYA cancer survivors is important for promoting cardiovascular health in this growing population.

Validation of the Lee-Jones theoretical model of fear of cancer recurrence among breast cancer survivors using a structural equation modeling approach.

OBJECTIVE: The Lee-Jones model posits that antecedent individual and interpersonal factors predicate the development of fear of cancer recurrence (FCR) through cognitive and emotional processing, which further to behavioral, emotional, and/or physiological responses. We analyzed data from FoRtitude, a FCR intervention grounded in the Lee-Jones FCR model, to evaluate associations between FCR antecedents, resources (e.g., breast cancer self-efficacy, BCSE) and psychological and behavioral consequences. METHODS: Women with breast cancer who completed treatment and reported clinically elevated levels of FCR were randomized into a 4-week online psychosocial intervention or contact control group. We assessed BCSE, FCR, and physical activity, anxiety and depression, or symptoms at baseline, 4 and 8 weeks. Separate structural equation models were constructed with both baseline data and change scores (baseline-8 weeks) to examine the pathways linking BCSE, FCR and: (1) physical activity; (2) anxiety and depression; and (3) symptoms (fatigue, sleep disturbance, cognitive concerns). RESULTS: At baseline, higher levels of BCSE were associated with lower levels of FCR. Higher FCR was associated with worse psychological effects and symptoms but not behavioral response. Change models revealed that an increase in BCSE was associated with a decrease in FCR at 8-week assessment, which was associated with reductions in psychological effects. A change in BCSE was also directly associated with reductions in psychological effects. CONCLUSIONS: Results support the Lee-Jones model as a foundation for FCR interventions among breast cancer survivors. Replicability among varied populations is needed to examine effects on behavioral outcomes of FCR such as health care utilization. CLINICAL TRIALS REGISTRATION: NCT03384992.

Qualitative similarities and distinctions between participants' experiences with a yoga intervention and an attention control.

PURPOSE: This manuscript aims to compare and contrast acceptability and perceived benefits of yoga-skills training (YST) and an empathic listening attention control (AC) in the Pro-You study, a randomized pilot trial of YST vs. AC for adults receiving chemotherapy infusions for gastrointestinal cancer. METHODS: Participants were invited for a one-on-one interview at week 14 follow-up, after completing all intervention procedures and quantitative assessments. Staff used a semi-structured guide to elicit participants' views on study processes, the intervention they received, and its effects. Qualitative data analysis followed an inductive/deductive approach, inductively identifying themes and deductively guided by social cognitive theory. RESULTS: Some barriers (e.g., competing demands, symptoms), facilitators (e.g., interventionist support, the convenience of clinic-based delivery), and benefits (e.g., decreased distress and rumination) were common across groups. YST participants uniquely described the importance of privacy, social support, and self-efficacy for increasing engagement in yoga. Benefits specific to YST included positive emotions and greater improvement in fatigue and other physical symptoms. Both groups described some self-regulatory processes, but through different mechanisms: self-monitoring in AC and the mind-body connection in YST. CONCLUSIONS: This qualitative analysis demonstrates that participant experiences in a yoga-based intervention or an AC condition reflect social cognitive and mind-body frameworks of self-regulation. Findings can be used to develop yoga interventions that maximize acceptability and effectiveness and to design future research that elucidates the mechanisms by which yoga is efficacious.

Patient-reported tolerability of adjuvant ipilimumab (3 or 10 mg/kg) versus high-dose interferon alfa-2b for resected high-risk stage III-IV melanoma in phase III trial E1609.

PURPOSE: Trial E1609 demonstrated superior overall survival with ipilimumab 3 mg/kg (ipi3) compared to high-dose interferon (HDI) for patients with resected high-risk melanoma. To inform treatment tolerability, we compared health-related quality of life (HRQoL), gastrointestinal (GI), and treatment-specific physical and cognitive/emotional symptoms. We also compared treatment-specific concerns between all arms. METHODS: We assessed HRQoL using the Functional Assessment of Cancer Therapy-General, physical and cognitive/emotional concerns using the FACT-Biologic Response Modifier subscale, and GI symptoms with the Functional Assessment of Chronic Illness Therapy-Diarrhea subscale pre-treatment and every 3 months. The primary outcome was the difference in HRQoL at 3 months between ipi3/ipi10 vs. HDI. RESULTS: 549 patients (n = 158 ipi3; n = 191 ipi10; n = 200 HDI) were analyzed. 3-month completion was 58.7%. Compared to HDI, ipilimumab patients reported better HRQoL (ipi3 = 87.5 ± 14.6 vs. HDI = 74.7 ± 15.4, p < .001; ipi10 = 84.9 ± 16.5 vs. HDI, p < .001) and fewer physical (ipi3 = 22.3 ± 4.6 vs. HDI = 17.1 ± 5.4, p < .001; ipi10 = 21.8 ± 5.0 vs. HDI p < .001) and cognitive/emotional (ipi3 = 18.6 ± 4.4 vs. HDI = 15.0 ± 5.3, p < .001; ipi10 = 17.7 ± 4.8 vs. HDI p < .001) concerns, but worse GI symptoms (ipi3 = 40.8 ± 5.0 vs. HDI = 42.2 ± 2.9, p = .011; ipi10 = 39.5 ± 7.0 vs. HDI, p < .001). Fewer ipilimumab patients reported worsening treatment-specific concerns (e.g., 52% of ipi3 and 58% of ipi10 reported worsening fatigue vs. 82% HDI, p's < .001). CONCLUSION: PROs demonstrated less toxicity of ipi3 compared to HDI and ipi10. Priorities for symptom management among patients receiving ipilimumab include GI toxicities, fatigue, weakness, appetite loss, arthralgia, and depression. TRIAL REGISTRATION: NCT01274338, January 11, 2011 (first posted date) https://clinicaltrials.gov/ct2/show/NCT01274338?term=NCT01274338&draw=2&rank=1 .

Fatigue and endocrine symptoms among women with early breast cancer randomized to endocrine versus chemoendocrine therapy: Results from the TAILORx patient-reported outcomes substudy.

BACKGROUND: TAILORx (Trial Assigning Individualized Options for Treatment) prospectively assessed fatigue and endocrine symptoms among women with early-stage hormone receptor-positive breast cancer and a midrange risk of recurrence who were randomized to endocrine therapy (E) or chemotherapy followed by endocrine therapy (CT+E). METHODS: Participants completed the Functional Assessment of Chronic Illness Therapy-Fatigue, the Patient-Reported Outcomes Measurement Information System-Fatigue Short Form, and the Functional Assessment of Cancer Therapy-Endocrine Symptoms at the baseline and at 3, 6, 12, 24, and 36 months. Linear regression was used to model outcomes on baseline symptoms, treatment, and other factors. RESULTS: Participants (n = 458) in both treatment arms reported greater fatigue and endocrine symptoms at early follow-up in comparison with the baseline. The magnitude of change in fatigue was significantly greater for the CT+E arm than the E arm at 3 and 6 months but not at 12, 24, or 36 months. The CT+E arm reported significantly greater changes in endocrine symptoms from the baseline to 3 months in comparison with the E arm; change scores were not significantly different at later time points. Endocrine symptom trajectories by treatment differed by menopausal status, with the effect larger and increasing for postmenopausal patients. CONCLUSIONS: Adjuvant CT+E was associated with greater increases in fatigue and endocrine symptoms at early time points in comparison with E. These differences lessened over time, and this demonstrated early chemotherapy effects more than long-term ones. Treatment arm differences in endocrine symptoms were more evident in postmenopausal patients. LAY SUMMARY: Participants in TAILORx (Trial Assigning Individualized Options for Treatment) with early-stage hormone receptor-positive breast cancer and an intermediate risk of recurrence were randomly assigned to endocrine or chemoendocrine therapy. Four hundred fifty-eight women reported fatigue and endocrine symptoms at the baseline and at 3, 6, 12, 24, and 36 months. Both groups reported greater symptoms at early follow-up versus the baseline. Increases in fatigue were greater for the chemoendocrine group than the endocrine group at 3 and 6 months but not later. The chemoendocrine group reported greater changes in endocrine symptoms in comparison with the endocrine group at 3 months but not later.

A randomized study of genetic education versus usual care in tumor profiling for advanced cancer in the ECOG-ACRIN Cancer Research Group (EAQ152).

BACKGROUND: Enthusiasm for precision oncology may obscure the psychosocial and ethical considerations associated with the implementation of tumor genetic sequencing. METHODS: Patients with advanced cancer undergoing tumor-only genetic sequencing in the National Cancer Institute Molecular Analysis for Therapy Choice (MATCH) trial were randomized to a web-based genetic education intervention or usual care. The primary outcomes were knowledge, anxiety, depression, and cancer-specific distress collected at baseline (T0), posteducation (T1) and after results (T2). Two-sided, 2-sample t tests and univariate and multivariable generalized linear models were used. RESULTS: Five hundred ninety-four patients (80% from NCI Community Oncology Research Program sites) were randomized to the web intervention (n = 293) or usual care (n = 301) before the receipt of results. Patients in the intervention arm had greater increases in knowledge (P for T1-T0 < .0001; P for T2-T0 = .003), but there were no significant differences in distress outcomes. In unadjusted moderator analyses, there was a decrease in cancer-specific distress among women (T0-T1) in the intervention arm but not among men. Patients with lower health literacy in the intervention arm had greater increases in cancer-specific distress and less decline in general anxiety (T0-T1) and greater increases in depression (T0-T2) in comparison with those receiving usual care. CONCLUSIONS: Web-based genetic education before tumor-only sequencing results increases patient understanding and reduces distress in women. Refinements to the intervention could benefit low-literacy groups and men.

Physician Perspectives on Reducing Curative Cancer Treatment Intensity for Populations Underrepresented in Clinical Trials.

BACKGROUND: Historically, clinical trials involved adding novel agents to standard of care to improve survival. There has been a shift to an individualized approach with testing less intense treatment, particularly in breast cancer where risk of recurrence is low. Little is known about physician perspectives on delivering less intense treatment for patients who are not well represented in clinical trials. METHODS: Open-ended, individual qualitative interviews with medical oncologists explored their perspectives on trials that test less intense treatment for patients with cancer, with a focus on breast cancer. Interviews were audio-recorded and transcribed. Four independent coders utilized a content analysis approach to analyze transcripts using NVivo. Major themes and exemplary quotes were extracted. RESULTS: Of the 39 participating physicians, 61.5% felt comfortable extrapolating, 30.8% were hesitant, and 7.7% would not feel comfortable extrapolating trial outcomes to underrepresented populations. Facilitators of comfort included the sentiment that "biology is biology" (such that the cancer characteristics were what mattered), the strength of the evidence, inclusion of subset analysis on underrepresented populations, and prior experience making decisions with limited data. Barriers to extrapolation included potential harm over the patient's lifetime, concerns about groups that had minimal participants, application to younger patients, and extending findings to diverse populations. Universally, broader inclusion in trials testing lowering chemotherapy was desired. CONCLUSIONS: The majority (92%) of physicians reported that they would de-implement treatment for patients poorly represented in clinical trials testing less treatment, while expressing concerns about applicability to specific subpopulations. Further work is needed to increase clinical trial representation of diverse populations to safely and effectively optimize treatment for patients with cancer. TRIAL REGISTRATION: NCT03248258.

Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer.

BACKGROUND: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).

Facilitators and barriers to reducing chemotherapy for early-stage breast cancer: a qualitative analysis of interviews with patients and patient advocates.

BACKGROUND: As the combination of systemic and targeted chemotherapies is associated with severe adverse side effects and long-term health complications, there is interest in reducing treatment intensity for patients with early-stage breast cancer (EBC). Clinical trials are needed to determine the feasibility of reducing treatment intensity while maintaining 3-year recurrence-free survival of greater than 92%. To recruit participants for these trials, it is important to understand patient perspectives on reducing chemotherapy. METHODS: We collected qualitative interview data from twenty-four patients with Stage II-III breast cancer and sixteen patient advocates. Interviews explored potential barriers and facilitators to participation in trials testing reduced amounts of chemotherapy. As the COVID-19 pandemic struck during data collection, seventeen participants were asked about the potential impact of COVID-19 on their interest in these trials. Interviews were audio-recorded and transcribed, and researchers used qualitative content analysis to code for dominant themes. RESULTS: Seventeen participants (42.5%) expressed interest in participating in a trial of reduced chemotherapy. Barriers to reducing chemotherapy included (1) fear of recurrence and inefficacy, (2) preference for aggressive treatment, (3) disinterest in clinical trials, (4) lack of information about expected outcomes, (5) fear of regret, and (6) having young children. Facilitators included (1) avoiding physical toxicity, (2) understanding the scientific rationale of reducing chemotherapy, (3) confidence in providers, (4) consistent monitoring and the option to increase dosage, (5) fewer financial and logistical challenges, and (6) contributing to scientific knowledge. Of those asked, nearly all participants said they would be more motivated to reduce treatment intensity in the context of COVID-19, primarily to avoid exposure to the virus while receiving treatment. CONCLUSIONS: Among individuals with EBC, there is significant interest in alleviating treatment-related toxicity by reducing chemotherapeutic intensity. Patients will be more apt to participate in trials testing reduced amounts of chemotherapy if these are framed in terms of customizing treatment to the individual patient and added benefit-reduced toxicities, higher quality of life during treatment and lower risk of long-term complications-rather than in terms of taking treatments away or doing less than the standard of care. Doctor-patient rapport and provider support will be crucial in this process.

How do patients interpret and respond to a single-item global indicator of cancer treatment tolerability?

BACKGROUND: There is increasing interest in patient-reported measures of cancer treatment tolerability. A global measure of bother, the FACT GP5 item ("I am bothered by side effects of treatment") is potentially useful for regulatory, research, and clinical use. To understand this item's appropriateness for capturing treatment tolerability, we conducted cognitive interviews on this item with 3 samples of cancer patients. METHODS: Patients with ovarian cancer (Study 1: N = 21; on treatment), lymphoma (Study 2: N = 14; on treatment), and colorectal or lung cancer (Study 3: N = 16; treatment naïve) were interviewed about GP5's understandability and relevance to their treatment side effects. What patients think about when answering GP5 was also assessed. In all studies, the interview included both structured and open-ended questions. Qualitative data were coded to extract themes and responses to structured questions were tallied. RESULTS: Most patients on treatment (Studies 1 and 2) reported that the GP5 item wording is appropriate (88%) and its meaning is clear (97%). They were very confident or confident in their response (97%) and stated that GP5 was relevant to their cancer experience (97%). When answering GP5, patients considered their treatment and specific side effects. A large proportion (40%) of the treatment-naïve (Study 3) patients reported that GP5 was not relevant to their cancer treatment, and the largest proportion responded to GP5 thinking of negative side effect expectancies. CONCLUSION: This study provides assurance that GP5 is a useful indicator of treatment tolerability, and is meaningful to people with cancer, especially once they have started treatment.

Study protocol for a hybrid type 1 effectiveness-implementation trial testing virtual tobacco treatment in oncology practices [Smokefree Support Study 2.0].

BACKGROUND: Persistent smoking among patients diagnosed with cancer is associated with adverse clinical outcomes, yet an evidence-based tobacco use intervention has not been well-integrated into cancer care in community oncology settings. This paper describes the protocol of a nation-wide clinical trial conducted by the ECOG-ACRIN National Cancer Institute (NCI) Community Oncology Research Program (NCORP) Research Base to assess the effectiveness of a virtual tobacco treatment intervention and the process of implementing tobacco treatment in NCORP community oncology settings. METHODS/DESIGN: This two-arm, multisite (n: 49 NCORP sites) hybrid type 1 effectiveness-implementation randomized controlled trial compares the effectiveness of a Virtual Intervention Treatment (VIT) versus an Enhanced Usual Control (EUC) among English and Spanish speaking patients recently diagnosed with cancer, reporting current smoking and receiving care at a participating NCORP Community or Minority/Underserved Site. The VIT includes up to 11 virtual counseling sessions with a tobacco treatment specialist and up to 12 weeks of nicotine replacement therapy (NRT). The EUC arm receives a referral to the NCI Quitline. The primary study outcome is biochemically confirmed 7-day point prevalence smoking abstinence. Moderators of treatment effect will be assessed. The study evaluates implementation processes from participating NCORP site staff via survey, administrative, and focus group data, including reach, acceptability, appropriateness, fidelity, feasibility, adoption, cost and sustainability outcomes. DISCUSSION: This trial will generate findings about the effectiveness of an evidence-based virtual tobacco treatment intervention targeting patients diagnosed with cancer and illuminate barriers and facilitators that influence implementing tobacco treatment into community oncology settings nationally. In the era of COVID-19, virtual care solutions are vital for maximizing access and utilization of tobacco treatment delivery. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03808818) on January 18th, 2019; Last update posted: May 21st, 2020.