Clinical Characteristics, Treatment Patterns, and Outcomes of Patients With Locally Advanced/Metastatic Hepatocellular Carcinoma Treated at the Veterans Health Administration.

PURPOSE: This study retrospectively reviewed the outcomes of patients with advanced hepatocellular carcinoma (HCC) receiving atezolizumab with bevacizumab (A + B) therapy at the Veterans Health Administration (VHA). PATIENTS AND METHODS: Patients with advanced HCC who received first-line systemic therapy with A + B at the VHA between December 1, 2019, and March 1, 2022, were selected from electronic medical records (EMR) using ICD-9 and ICD-10 codes. Abstractors reviewed the EMR of the patients from their index date of A + B initiation until death or their last VHA visit, with the study period ending on January 31, 2023. The chi-square test was used to compare rates, and the Mann-Whitney test was used to compare medians. RESULTS: A total of 332 patients met the study criteria. The median age was 67 years; 99% were male, 63% were non-Hispanic Whites, 26% were Black, and 66% had an Eastern Cooperative Oncology Group performance status of ≥1. 84% had child Pugh score (CPS) class A, 16% had CPS classes B and C, 62% had a grade 2 albumin-bilirubin score, 56% had HCC caused by viral hepatitis, 80% had cirrhosis, and 67% had received prior local therapies. The 6-month progression-free survival (PFS) was 59%, while the 1-year PFS rate was 36%. Overall survival (OS) at 1-year was 52% in our study. CONCLUSION: In real world, despite having similar PFS as the phase III IMbrave 150 trial, our OS at 12 months was lower (52% vs. 67%) because our study included a higher proportion of elderly patients with moderate liver dysfunction and a 40% non-White. This study provided real-world outcomes that differed from the study population in a pivotal trial.

Health Equity in Patients Receiving Durvalumab for Unresectable Stage III Non-Small Cell Lung Cancer in the US Veterans Health Administration.

BACKGROUND: Real-world evidence is limited regarding the relationship between race and use of durvalumab, an immunotherapy approved for use in adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This study aimed to evaluate if durvalumab treatment patterns differed by race in patients with unresectable stage III NSCLC in a Veterans Health Administration (VHA) population. MATERIALS AND METHODS: This was a retrospective analysis of White and Black adults with unresectable stage III NSCLC treated with durvalumab presenting to any VHA facility in the US from January 1, 2017, to June 30, 2020. Data captured included baseline characteristics and durvalumab treatment patterns, including treatment initiation delay (TID), interruption (TI), and discontinuation (TD); defined as CRT completion to durvalumab initiation greater than 42 days, greater than 28 days between durvalumab infusions, and more than 28 days from the last durvalumab dose with no new durvalumab restarts, respectively. The number of doses, duration of therapy, and adverse events were also collected. RESULTS: A total of 924 patients were included in this study (White = 726; Black = 198). Race was not a significant factor in a multivariate logistic regression model for TID (OR, 1.39; 95% CI, 0.81-2.37), TI (OR, 1.58; 95% CI, 0.90-2.76), or TD (OR, 0.84; 95% CI, 0.50-1.38). There were also no significant differences in median (interquartile range [IQR]) number of doses (White: 15 [7-24], Black: 18 [7-25]; P = .25) or median (IQR) duration of therapy (White: 8.7 months [2.9-11.8], Black: 9.8 months [3.6-12.0]; P = .08), although Black patients were less likely to experience an immune-related adverse event (28% vs. 36%, P = .03) and less likely to experience pneumonitis (7% vs. 14%, P < .01). CONCLUSION: Race was not found to be linked with TID, TI, or TD in this real-world study of patients with unresectable stage III NSCLC treated with durvalumab at the VHA.

Incidence of invasive fungal infections in patients with chronic lymphocytic leukemia receiving ibrutinib within the veteran's healthcare administration.

PURPOSE: Ibrutinib is a tyrosine kinase inhibitor that is increasingly prescribed in chronic lymphocytic leukemia (CLL). Invasive fungal infections (IFIs) have been reported early after ibrutinib initiation. Timing of IFIs is within 6 months and commonly reported fungal infections include Cryptococcus, Aspergillus, and Pneumocystis. Currently, there are no recommendations for routine prophylaxis against IFIs in patients receiving ibrutinib for CLL. OBJECTIVE: The objective of this study was to evaluate the incidence of IFIs in patients receiving ibrutinib for CLL in first-line and relapsed/refractory (R/R) settings. METHODS: This was a retrospective, cohort study of patients diagnosed with CLL and initiated on ibrutinib in the Veterans Health Administration (VHA) from October 1, 2013 to March 31, 2018. Patients were included if diagnosed with a proven or probable IFI from the start date of ibrutinib to 30 days after the last dose of ibrutinib. RESULTS: Fourteen out of 1069 patients met inclusion criteria for IFI while on ibrutinib for CLL. All patients included were male with a median age of 78 years. Fifty percent of patients were initiated on ibrutinib within 3 months of last chemotherapy. IFIs occurred within 3 months (50%) and 6 months (71%) of ibrutinib initiation. Seventy-one percent of patients were continued on ibrutinib with concurrent IFI diagnosis. CONCLUSION: The reported IFI incidence of 1.3% is comparable to current estimates of 1.2%. Future studies should examine the relationship of ibrutinib and incidence of IFIs in first-line and R/R settings in addition to identifying clinical risk factors predisposing patients to IFIs.

Hyperviscosity Syndrome in Undifferentiated Connective Tissue Disease: A Diagnostic and Therapeutic Challenge.

Hyperviscosity is an uncommon manifestation of various underlying diseases. Rapid diagnosis and management of the underlying disease is crucial to prevent significant complications, including hypertension, cerebral vascular accidents, pulmonary embolism, bowel ischemia, and ophthalmologic pathologies. Although the acute management of complications arising from hyperviscosity is relatively straightforward, identifying and treating the underlying cause can prove difficult. This case highlights the difficulties of establishing a diagnosis and initiating appropriate management for a patient with hyperviscosity syndrome in a suspected rheumatologic disorder.

The Impact of Time From Diagnosis to Initiation of Chemotherapy on Survival of Patients With Newly Diagnosed Diffuse Large B-Cell Lymphoma in the Veterans Health Administration.

INTRODUCTION: Our retrospective study evaluates the impact of time from diagnosis to treatment (TDT) on outcomes of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) treated within the Veterans Health Administration (VHA). METHODS: VHA patients diagnosed with DLBCL between 2011 and 2019 were included, while those with primary central nervous system lymphoma were excluded. The median overall survival and progression-free survival were estimated with the Kaplan-Meier method. Univariate, bivariate, and multivariable analyses were performed using the Cox proportional hazards model. The odds ratio for refractory outcomes was calculated using logistic regression. RESULTS: A total of 2448 patients were included. The median time from diagnosis to treatment of the cohort was 19 days. When comparing median progression-free survival, median overall survival, and the 2-year overall survival between the group that started treatment within 1 week and each of the other groups individually, there was a significant difference favoring improved survival in all groups with a TDT longer than 1 week (P < .0001). These patients also had a lower odds ratio for refractory outcomes. On multivariable analysis, TDT remained an independent prognostic factor. CONCLUSION: Our study shows that a TDT equal to or less than 1 week is associated with adverse clinical factors, worse outcomes, and response in DLBCL, even after adjusting for multiple known poor prognostic factors. This was the first time that response to first-line therapy was correlated to time to treatment. Our findings support ongoing efforts to improve currently standardized prognostic tools and the incorporation of TDT into clinical trials to avoid selection bias.

The impact of race and ethnicity on diffuse large B-cell lymphoma outcomes within the veterans health administration (VHA).

We performed a retrospective chart review of 6266 randomly selected DLBCL patients treated in the VHA nationwide between 1/1/2011 and 12/31/2021. The 3178 patients who met inclusion criteria were predominantly male (97%) and white (75%). Median age of diagnosis for Black patients was 63 years vs 69 years for the entire cohort (p < 0.001). However, patients in each race/ethnicity subgroup presented with similar rates of stage I/II and III/IV disease, IPI score, cell of origin and HIT status. Outcomes analysis revealed similar treatment, response rates, median overall survival, and 1-, 3-, and 5-year survival across all subgroups. Hispanic patients had a 21% lower risk of death (HR = 0.79) than white patients, and Black patients had no significant difference in survival (HR = 0.98). This large retrospective study shows that when standard of care therapy is given within an equal access system, short-term treatment and survival outcomes are the same for all races.

Health disparity in use of novel agents for first-line therapy in Black and White patients with chronic lymphocytic leukemia in the Department of Veterans Affairs.

BACKGROUND: Novel agents (NAs) (ibrutinib, idelalisib, and venetoclax) were first introduced in 2013 as therapeutic options to treat chronic lymphocytic leukemia (CLL). OBJECTIVES: To determine if the uptake of NAs for first-line treatment was similar in Black and White patients with CLL treated in the Department of Veterans Affairs (VA). METHODS: We conducted a retrospective cohort study including adults with CLL managed in the VA from October 1, 2013, to September 30, 2017. Descriptive statistics were used to summarize demographic data, and appropriate bivariable statistical tests were used to compare NA use, baseline characteristics, health outcomes, and complications. A multivariable logistic regression model was used to identify factors associated with uptake of NAs. The study included 565 patients; 86% were White and 14% were Black. Black patients were younger than White patients (median age [66 vs 69 years; P < 0.01]) but had similar median baseline Charlson comorbidity scores (4 vs 5). RESULTS: Overall, Black patients were less likely to receive NAs than White patients (14% vs 26%; P = 0.02). The gap narrowed over the study period: 4% vs 17% (2014), 13% vs 25% (2015), 17% vs 33% (2016), and 31% vs 33% (2017). Black race (P = 0.02) and fiscal year (P < 0.01) were the only variables significantly associated with NA use in the multivariable model. Health outcomes and most complications were similar for Black and White patients despite the difference in prescribing patterns. CONCLUSIONS: This is the first study to identify a potential health disparity with respect to use of NAs among Black and White patients with CLL treated in the VA. Fortunately, health outcomes and most complications were similar for Black and White patients despite the difference in prescribing patterns. DISCLOSURES: Funding for the study was provided by AstraZeneca as a research grant to the Foundation for Advancing Veterans' Health Research (FAVHR), a non-profit entity within the Audie L. Murphy Veterans Hospital, San Antonio, TX. Drs Nooruddin and Frei have received research grants (paid to FAVHR) from AstraZeneca in the last 3 years. Ms Ryan is an employee of AstraZeneca. The views expressed in this article are those of the authors and do not necessarily represent the views of the Department of Veterans Affairs, the National Institutes of Health, or the authors' affiliated institutions.

Durvalumab Treatment Patterns for Patients with Unresectable Stage III Non-Small Cell Lung Cancer in the Veterans Health Administration (VHA): A Nationwide, Real-World Study.

BACKGROUND: Durvalumab is approved for the treatment of adults with unresectable stage III non-small cell lung cancer (NSCLC) post-chemoradiotherapy (CRT). This real-world study describes patient characteristics and durvalumab treatment patterns (number of doses and therapy duration; treatment initiation delays, interruptions, discontinuations, and associated reasons) among VHA-treated patients. METHODS: This was a retrospective cohort study of adults with unresectable stage III NSCLC receiving durvalumab at the VHA between 1 January 2017 and 30 June 2020. Patient characteristics and treatment patterns were presented descriptively. RESULTS: A total of 935 patients were included (median age: 69 years; 95% males; 21% Blacks; 46% current smokers; 16% ECOG performance scores ≥ 2; 50% squamous histology). Durvalumab initiation was delayed in 39% of patients (n = 367). Among the 200 patients with recorded reasons, delays were mainly due to physician preference (20%) and CRT toxicity (11%). Overall, patients received a median (interquartile range) of 16 (7-24) doses of durvalumab over 9.0 (2.9-11.8) months. Treatment interruptions were experienced by 19% of patients (n = 180), with toxicity (7.8%) and social reasons (2.6%) being the most cited reasons. Early discontinuation occurred in 59% of patients (n = 551), largely due to disease progression (24.2%) and toxicity (18.2%). CONCLUSIONS: These real-world analyses corroborate PACIFIC study results in terms of the main reasons for treatment discontinuation in a VHA population with worse prognostic factors, including older age, predominantly male sex, and poorer performance score. One of the main reasons for durvalumab initiation delays, treatment interruptions, or discontinuations was due to toxicities. Patients could benefit from improved strategies to prevent, identify, and manage CRT and durvalumab toxicities timely and effectively.

Outcomes in chronic lymphocytic leukemia patients on novel agents in the US Veterans Health Administration System.

The US veteran population has a high proportion of chronic lymphocytic leukemia (CLL) risk factors. Using the Veterans Health Administration (VHA) population, we conducted a retrospective chart review of 1205 CLL patients who initiated treatment with a novel oral agent. For 1L ibrutinib, 33% (n = 107) discontinued therapy during the study, of which 64% discontinued due to adverse events (AEs). For relapsed/refractory (R/R) ibrutinib, 35% (n = 262) discontinued therapy, of which 63% discontinued due to AEs. For R/R venetoclax, 31% (n = 27) discontinued therapy, of which 41% were due to AEs. For idelalisib, 84% (n = 41) discontinued therapy, of which 54% were due to AEs. This real-world study suggests that AEs play an important role in dose reductions and discontinuations; however, physician inexperience in using these drugs when they were first introduced could be part of what is leading to these negative outcomes.

West Nile Encephalitis, an Unusual Infection in a Chronic Lymphocytic Leukemia Patient.

CNS involvement by CLL is a rare occurrence, usually happening in the context of a transformation to a more aggressive lymphoma in what is known as Richter's transformation. We report a patient with active CLL who developed confusion and was found to have West Nile encephalitis that initially mimicked CNS involvement by CLL. The patient recovered with supportive treatment and later restarted ibrutinib therapy. This case illustrates the importance of maintaining a broad differential among cancer patients with new onset confusion as well as that of questioning malignant infiltration of CNS when there is concomitant active CNS infection.

Concepts and definitions for "actively dying," "end of life," "terminally ill," "terminal care," and "transition of care": a systematic review.

CONTEXT: The terms "actively dying," "end of life," "terminally ill," "terminal care," and "transition of care" are commonly used but rarely and inconsistently defined. OBJECTIVES: We conducted a systematic review to examine the concepts and definitions for these terms. METHODS: We searched MEDLINE, PsycINFO, Embase, and CINAHL for published peer-reviewed articles from 1948 to 2012 that conceptualized, defined, or examined these terms. Two researchers independently reviewed each citation for inclusion and then extracted the concepts/definitions when available. We also searched 10 dictionaries, four palliative care textbooks, and 13 organization Web sites, including the U.S. Federal Code. RESULTS: One of 16, three of 134, three of 44, two of 93, and four of 17 articles defined or conceptualized actively dying, end of life, terminally ill, terminal care, and transition of care, respectively. Actively dying was defined as "hours or days of survival." We identified two key defining features for end of life, terminally ill, and terminal care: life-limiting disease with irreversible decline and expected survival in terms of months or less. Transition of care was discussed in relation to changes in 1) place of care (e.g., hospital to home), 2) level of professions providing the care (e.g., acute care to hospice), and 3) goals of care (e.g., curative to palliative). Definitions for these five terms were rarely found in dictionaries, textbooks, and organizational Web sites. However, when available, the definitions were generally consistent with the concepts discussed previously. CONCLUSION: We identified unifying concepts for five commonly used terms in palliative care and developed a preliminary conceptual framework toward building standardized definitions.

Trastuzumab emtansine and stereotactic radiosurgery: an unexpected increase in clinically significant brain edema.

BACKGROUND: In the last 10 years, multiple new targeted agents have been developed for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer. Up to 55% of patients with HER2+ breast cancer will develop brain metastases requiring some form of radiation therapy. The interaction between radiation and these targeted agents is unknown and previously unreported. METHODS: In this series, we describe 4 patients who developed clinically significant brain edema at sites of treated brain metastases. These patients were treated with stereotactic radiosurgery and trastuzumab emtansine, the newest FDA-approved agent for metastatic HER2+ breast cancer. Additionally, we present rates of clinically significant radiation necrosis among all breast cancer patients treated during this same time period. RESULTS: Using previously published clinical and preclinical data, we then hypothesize possible mechanisms for this striking interaction. CONCLUSION: Increased awareness of potential interactions between targeted agents and radiation to the brain is crucial.

Association between serum cortisol and testosterone levels, opioid therapy, and symptom distress in patients with advanced cancer.

CONTEXT: Patients with advanced cancer often experience symptoms such as pain, anorexia, and fatigue. Opioid therapy for the management of cancer pain may result in neurohormonal dysfunction that may contribute to a patient's symptom burden. OBJECTIVES: To examine the association between serum cortisol and testosterone levels, opioid therapy, and symptom distress in patients with cancer. METHODS: A retrospective chart review was performed on 77 consecutive patients with advanced cancer referred for symptoms of fatigue or cachexia. We collected information regarding cortisol levels (am or random), testosterone levels (men only), morphine equivalent daily dose (MEDD), and symptom severity measured by the Edmonton Symptom Assessment Scale. Nonparametric correlation analysis was performed. RESULTS: The median age was 63 years (range 24-79), and 62% were men (n=48). Most patients had gastrointestinal (n=33, 43%) or thoracic (n=21, 27%) malignancies and were Caucasian (n=46, 60%). The median random cortisol level was 19.1 µg/dL (Q1-Q3, 13.4-23.8 [normal, 4.3-22.4]), which correlated with MEDD (Spearman coefficient, 0.25, P=0.032) and symptoms including pain (0.50, P<0.001), fatigue (0.29, P=0.012), nausea (0.34, P=0.003), depression (0.24, P=0.032), and anxiety (0.25, P=0.031). Pain and nausea remained significant after Bonferroni correction. Median morning cortisol level (n=28) was 20.6 µg/dL (Q1-Q3, 16.6-25.4) and significantly correlated with pain (0.55, P=0.003) after Bonferroni correction. Patients with a MEDD <30 mg/day had a mean random cortisol level of 16.6 µg/dL, whereas patients with a MEDD ≥ 30 mg/day had a mean random cortisol level of 20.6 µg/dL (P=0.01). In 44 male patients with cancer, MEDD was inversely correlated with the total testosterone level (-0.52, P=0.001). CONCLUSION: In patients with advanced cancer, elevated random cortisol levels were associated with pain and opioid use, although abnormally low levels of cortisol were found to be infrequent. Patients on higher opioid therapy (MEDD >30) had increased cortisol levels, and male patients had lower testosterone levels. Our study suggests that opioid therapy in patients with advanced cancer may inhibit gonadal function while sparing the adrenal axis. Future studies are needed.

Clinical outcomes and contributors to weight loss in a cancer cachexia clinic.

BACKGROUND: Cancer cachexia is considered intractable, with few therapeutic options. Secondary nutrition impact symptoms (S-NIS) such as nausea may further contribute to weight loss by decreasing nutrient intake. In addition, treatable metabolic abnormalities such as hypogonadism, vitamin B12 deficiency, hypothyroidism, and hypoadrenalism could exacerbate anorexia and muscle wasting in patients with cancer cachexia. We determined the frequency and type of contributors to appetite and weight loss, and the effect of the cachexia clinic on clinical outcomes. METHODS: Review of 151 consecutive patients referred to a cachexia clinic. All received dietary counseling and exercise recommendations. Assessments included weight, body mass index (BMI), S-NIS, resting energy expenditure by indirect calorimetry, serum thyroid stimulating hormone (TSH), cortisol, total testosterone, and vitamin B12. RESULTS: Median weight loss in the 100 days before referral was 9% (4%-13%); median BMI at presentation was 20.8. Median number of S-NIS was 3 (2-4), most commonly treated by metoclopramide, laxatives, and antidepressants. Forty-one percent (24/59) of patients were hypermetabolic and 73% (52/71) of males hypogonadic, whereas hypoadrenalism (0/101, 0%), hypothyroidism (4/113, 4%), and low vitamin B12 (3/107, 3%) were uncommon. Poor appetite and weight loss before referral (r = 0.18, p = 0.036) were associated with increased S-NIS (r = 0.22, p = 0.008). Appetite improved (p < 0.001) and 31/92 (34%) of patients returning for a second visit gained weight. CONCLUSIONS: Patients had a high frequency of multiple S-NIS, hypogonadism, and hypermetabolism. A combination of simple pharmacological and nonpharmacological interventions improved appetite significantly, and increased weight in one third of patients who were able to return for follow-up. Cachexia clinics are feasible and effective for many patients with advanced cancer.

Associations among hypogonadism, C-reactive protein, symptom burden, and survival in male cancer patients with cachexia: a preliminary report.

CONTEXT: Cachexia is characterized by muscle wasting, anorexia, and elevated inflammatory markers. In patients without cancer, hypogonadism is associated with lower lean body mass, increased symptom burden, and decreased survival. Hypogonadism in cancer cachexia could exacerbate symptoms, facilitate a proinflammatory state, and decrease survival. OBJECTIVES: To explore the relationships among these factors, a retrospective study of male cancer patients was conducted. METHODS: The charts of 98 consecutive male patients referred to a cachexia clinic at a comprehensive cancer center were reviewed. All patients reported weight loss of >5% within the preceding six months; the median age was 60 years. Fifty-seven (58%) had serum C-reactive protein (CRP), and 68 (69%) had total testosterone evaluated. Symptoms were evaluated by the Edmonton Symptom Assessment Scale. RESULTS: Median CRP was 20mg/L, and median testosterone level was 185 ng/dL (6.42 nmol/L) (normal > or = 240 ng/dL or 8.36 nmol/L). There was an inverse correlation between testosterone and CRP levels (P<0.01). Lower testosterone was associated with increased dyspnea and insomnia (P<0.05). Poor appetite and insomnia (P<0.05) correlated with elevated CRP. Survival of patients with testosterone levels < or = 185 ng/dL (6.42 nmol/L) was decreased compared with that of those with levels >185 ng/dL (13 vs. 62 weeks, P=0.004). Patients with CRP levels >10mg/L had decreased survival compared with those with levels < or = 10mg/L (15 vs. 46 weeks, P=0.01). The combination of hypogonadism and elevated CRP was associated with poorer prognosis. Elevated CRP levels were associated with increased symptom burden and decreased survival. Low testosterone was associated with decreased survival and correlated inversely with CRP levels, dyspnea, and insomnia. CONCLUSION: Our preliminary results suggest that testosterone and CRP may be additive or synergistic as markers for survival in male patients and could be useful in future prognostic models.