Characterization of time toxicity in older patients with metastatic breast cancer.

PURPOSE: Recognizing that receiving healthcare can be time intensive and burdensome, time toxicity has been conceptualized as the time spent by patients seeking healthcare. This study investigates the association between age at diagnosis and time toxicity for patients with Metastatic Breast Cancer (MBC) and identifies major components of care that confer the greatest time toxicity. METHODS: We conducted a retrospective cohort study among patients with MBC aged 67 or older using the SEER-Medicare database. We assessed time toxicity using the number of encounter days patients interacted with the healthcare system per 100 days, within the first year of starting cancer treatment. We used a Poisson model to analyze the association between age and encounter days, adjusting for clinical and sociodemographic factors. We stratified the mean encounter days for each age cohort by treatment types. FINDINGS: The final sample included 2949 patients; 51.4% were between 70 and 79 years old, and 81.3% were white. Although unadjusted analysis showed an association between older age and more encounter days (Rate Ratio (RR) 1.12; 95% CI 1.02, 1.22), there was no significant association after adjusting for comorbidities and treatment type. Patients with more than three comorbidities had significantly higher encounter days compared to those without comorbidities [RR 1.36 (95% CI 1.26, 1.46)]. Receipt of radiotherapy [RR: 1.45 95% CI (1.37, 1.54)] was associated with more encounter days compared to not receiving radiotherapy, while receipt of bone-modifying agents was associated with fewer encounter days compared to not using Bone modifying agents [RR 0.75 (95% CI 0.70, 0.79)]. CONCLUSION: Our study identified comorbidities and cancer treatment modality, including radiotherapy, as the factors affecting time toxicity in older patients with MBC. Assessment of an individual's comorbid medical conditions and types of treatment planned are crucial to understanding age-related impacts on encounter days and to support shared decision making in older patients.

Risk Model Development and Validation in Clinical Oncology: Lessons Learned.

Reliable risk models can greatly facilitate patient-centered inferences and decisions. Herein we summarize key considerations related to risk modeling in clinical oncology. Often overlooked challenges include data quality, missing data, effective sample size estimation, and selecting the variables to be included in the risk model. The stability and quality of the model should be carefully interrogated with particular emphasis on rigorous internal validation.

Real-World Impact of Prophylactic Growth Factor Use on Timing of Febrile Neutropenia and Infection After High-Risk Chemotherapy.

BACKGROUND: Prophylactic growth-factor therapy with granulocyte colony-stimulating factor (G-CSF) reduces the risk of febrile neutropenia (FN) in patients with breast cancer initiating myelosuppressive chemotherapy. However, little is known about the protective benefit early in the chemotherapy cycle. METHODS: To assess the relationship between G-CSF prophylaxis and incidence of FN/infection in week 1 versus beyond week 1 of the first chemotherapy cycle, a retrospective study was conducted using Medicare claims from 2005 through 2020 among patients with breast cancer initiating high-risk chemotherapy. Two cohorts were compared based on G-CSF prophylaxis within 3 days following chemotherapy initiation. The primary outcome was FN or infection, defined as hospitalization with neutropenia, fever, or infection diagnosis. Secondary outcomes were a stricter definition of FN and infection-related hospitalization. Unadjusted and regression-adjusted proportions of patients experiencing each outcome during week 1 versus beyond week 1 of the first chemotherapy cycle were compared. RESULTS: Of 78,810 patients meeting all inclusion criteria (>98% female; mean age, 69 years), 79% initiated TC (docetaxel/cyclophosphamide), 14% TCH (docetaxel/carboplatin/trastuzumab), and 7% TAC (docetaxel/doxorubicin/cyclophosphamide). Among patients receiving G-CSF (74%), incidence of first-cycle FN/infection was lower compared with patients not receiving G-CSF (overall, 6% vs 13%; TAC, 12% vs 19%; TC, 6% vs 12%; TCH, 5% vs 15%). However, patients who received G-CSF were generally more likely to experience FN/infection in week 1 (adjusted odds ratio [aOR], 1.24 for all; 1.73 for TAC; 1.35 for TC; and 0.76 for TCH). Results were similar for strictly defined FN (overall aOR, 1.29 for week 1 and 0.12 for beyond week 1) and infection-related hospitalization (overall aOR, 1.33 for week 1 and 0.27 for beyond week 1). CONCLUSIONS: Overall, the rates of chemotherapy-related FN and infection in week 1 of the first chemotherapy cycle are similar for patients receiving and not receiving G-CSF, suggesting continued risk in week 1 despite prophylactic G-CSF.

Rivaroxaban for Thromboprophylaxis in High-Risk Ambulatory Patients with Cancer.

BACKGROUND: Ambulatory patients receiving systemic cancer therapy are at varying risk for venous thromboembolism. However, the benefit of thromboprophylaxis in these patients is uncertain. METHODS: In this double-blind, randomized trial involving high-risk ambulatory patients with cancer (Khorana score of ≥2, on a scale from 0 to 6, with higher scores indicating a higher risk of venous thromboembolism), we randomly assigned patients without deep-vein thrombosis at screening to receive rivaroxaban (at a dose of 10 mg) or placebo daily for up to 180 days, with screening every 8 weeks. The primary efficacy end point was a composite of objectively confirmed proximal deep-vein thrombosis in a lower limb, pulmonary embolism, symptomatic deep-vein thrombosis in an upper limb or distal deep-vein thrombosis in a lower limb, and death from venous thromboembolism and was assessed up to day 180. In a prespecified supportive analysis involving the same population, the same end point was assessed during the intervention period (first receipt of trial agent to last dose plus 2 days). The primary safety end point was major bleeding. RESULTS: Of 1080 enrolled patients, 49 (4.5%) had thrombosis at screening and did not undergo randomization. Of the 841 patients who underwent randomization, the primary end point occurred in 25 of 420 patients (6.0%) in the rivaroxaban group and in 37 of 421 (8.8%) in the placebo group (hazard ratio, 0.66; 95% confidence interval [CI], 0.40 to 1.09; P = 0.10) in the period up to day 180. In the prespecified intervention-period analysis, the primary end point occurred in 11 patients (2.6%) in the rivaroxaban group and in 27 (6.4%) in the placebo group (hazard ratio, 0.40; 95% CI, 0.20 to 0.80). Major bleeding occurred in 8 of 405 patients (2.0%) in the rivaroxaban group and in 4 of 404 (1.0%) in the placebo group (hazard ratio, 1.96; 95% CI, 0.59 to 6.49). CONCLUSIONS: In high-risk ambulatory patients with cancer, treatment with rivaroxaban did not result in a significantly lower incidence of venous thromboembolism or death due to venous thromboembolism in the 180-day trial period. During the intervention period, rivaroxaban led to a substantially lower incidence of such events, with a low incidence of major bleeding. (Funded by Janssen and others; CASSINI ClinicalTrials.gov number, NCT02555878.).

Mortality in hospitalized patients with cancer and coronavirus disease 2019: A systematic review and meta-analysis of cohort studies.

BACKGROUND: Heterogeneous evidence exists on the effect of coronavirus disease 2019 (COVID-19) on the clinical outcomes of patients with cancer. METHODS: A systematic review was performed using the Medline, Embase, and CENTRAL databases and the World Health Organization Novel Coronavirus website to identify studies that reported mortality and characteristics of patients with cancer who were diagnosed with COVID-19. The primary study outcome was mortality, defined as all-cause mortality or in-hospital mortality within 30 days of initial COVID-19 diagnosis. The pooled proportion of mortality was estimated using a random-effects model, and study-level moderators of heterogeneity were assessed through subgroup analysis and metaregression. RESULTS: Among 2922 patients from 13 primarily inpatient studies of individuals with COVID-19 and cancer, the pooled 30-day mortality rate was 30% (95% CI, 25%-35%). The overall pooled 30-day mortality rate among 624 patients from 5 studies that included a mixture of inpatient and outpatient populations was 15% (95% CI, 9%-22%). Among the hospitalized studies, the heterogeneity (I2 statistic) of the meta-analysis remained high (I2 , 82%). Cancer subtype (hematologic vs solid), older age, male sex, and recent active cancer therapy each partially explained the heterogeneity of mortality reporting. In multivariable metaregression, male sex, along with an interaction between the median patient age and recent active cancer therapy, explained most of the between-study heterogeneity (R2 , 96%). CONCLUSIONS: Pooled mortality estimates for hospitalized patients with cancer and COVID-19 remain high at 30%, with significant heterogeneity across studies. Dedicated community-based studies are needed in the future to help assess overall COVID-19 mortality among the broader population of patients with cancer.

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.

BACKGROUND: Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. METHODS: In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. FINDINGS: Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. INTERPRETATION: Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. FUNDING: American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Challenges and Opportunities for COVID-19 Vaccines in Patients with Cancer.

Given the rapidly expanding global spread of the SARS-Co-V-2 virus and the expanding number of individuals with the serious and potentially fatal illness, COVID-19, there is an urgent need for safe and effective vaccines. Based on compelling evidence that patients with cancer are at increased risk for greater morbidity and mortality with COVID-19, several professional organizations have provided early guidance on the role of COVID-19 vaccines in patients with malignant disease. In this commentary we review the available data on the efficacy and safety of the approved and forthcoming vaccines in patients with cancer. Based on a review of the totality of available evidence, we recommend that most patients with cancer should receive the recommended dose and schedule of one of the COVID-19 vaccines when available. We encourage industry, regulators and professional research organizations to carefully track the efficacy and safety of COVID-19 vaccination in patients with cancer in the real world setting and routinely report unanticipated adverse events and signs of loss of efficacy. Particular attention is needed for patients on active cancer therapy to carefully evaluate efficacy and safety in relationship to the timing of vaccination relative to that of active cancer treatment and immunosuppression.

Opportunities and Challenges of Observational Studies and Randomized Controlled Trials for Evaluating the Therapeutic Efficacy of COVID-19 Convalescent Plasma.

Large randomized controlled trials (RCTs) remain the gold standard for evaluating treatment efficacy. However, observational studies, including non-randomized cohort studies, as well as small RCTs have gained increasing attention especially during the SARS-CoV-2 pandemic where critical evaluation of limited therapeutic options are sought to improve patient care while awaiting results for subsequent RCTs. As the authors have previously discussed, RCTs and observational studies are complementary approaches which often appear synergistic with one another. While not all real-world studies are the same, the results of observational studies are notoriously subject to both known and unknown confounding factors. The utilization of COVID-19 Convalescent Plasma is a timely illustration of evaluating the efficacy and safety of a COVID-19 therapy given the dangerous and often lethal effects of the virus and the limited approved therapeutic options for the disease. While awaiting the results of large RCTS of convalescent plasma, serval observational cohorts and small RCTs have attempted to assess the efficacy and safety of this approach with very mixed results. Among the likely reasons for this failure to provide a definitive answer concerning the value of convalescent plasma are the many limitations inherent to addressing treatment efficacy in non-randomized studies. While such studies are often able to capture information on large numbers of individuals rapidly, it is important to understand that although larger numbers may enhance the precision of estimates provided, larger numbers, in and of themselves, do not increase the accuracy of estimates due to patient selection and other biases. At the same time, both observational studies and small RCTS are at risk for publication bias due to investigator, reviewer and editorial bias toward positive studies. In this commentary we discuss the advantages and limitations of these methodologic approaches when addressing urgently needed evidence on the effectiveness and safety of therapies in a crisis such as the COVID-19 pandemic.

Outcomes of Patients with Sarcoma and COVID-19 Infection: A Single Institution Cohort Analysis.

Outcomes for patients (pts) with sarcoma and COVID-19 are unknown. This is a single institution retrospective study of adults with sarcoma and COVID-19. Ten pts [median age 60 (range 24-69)] were identified. Five were hospitalized; two died from COVID-19 complications; another died from sarcoma. Time between last systemic treatment dose and COVID-19 diagnosis was 6-41 days in pts who died. 5 underwent prior radiation (RT); time between RT and COVID-19 diagnosis was 20-62 days for pts who died. All three pts with WBC differential data (two died) were lymphopenic. Efforts to capture outcomes for a larger cohort are urgently needed.

Cost-effectiveness analysis of low-dose direct oral anticoagulant (DOAC) for the prevention of cancer-associated thrombosis in the United States.

BACKGROUND: Randomized controlled trials (RCTs) have demonstrated that low-dose direct oral anticoagulants (DOACs), including rivaroxaban and apixaban, may help reduce the incidence of cancer-associated venous thromboembolism (VTE). METHODS: A cost-utility analysis was performed from the health sector perspective using a Markov state-transition model in patients with cancer who are at intermediate-to-high risk for VTE. Transition probability, relative risk, cost, and utility inputs were obtained from a meta-analysis of the RCTs and relevant epidemiology studies. Differences in cost, quality-adjusted life-years (QALYs), and the incremental cost-effectiveness ratio (ICER) per patient were calculated over a lifetime horizon. One-way, probabilistic, and scenario sensitivity analyses were conducted. RESULTS: In patients with cancer at intermediate-to-high risk for VTE, treatment with low-dose DOAC thromboprophylaxis for 6 months, compared with placebo, was associated with 32 per 1000 fewer VTE and 11 per 1000 more major bleeding episodes over a lifetime. The incremental cost and QALY increases were $1445 and 0.12, respectively, with an ICER of $11,947 per QALY gained. Key drivers of ICER variations included the relative risks of VTE and bleeding as well as drug cost. This strategy was 94% cost effective at the threshold of $50,000 per QALY. The selection of patients with Khorana scores ≥3 yielded the greatest value, with an ICER of $5794 per QALY gained. CONCLUSIONS: Low-dose DOAC thromboprophylaxis for 6 months appears to be cost-effective in patients with cancer who are at intermediate-to-high risk for VTE. The implementation of this strategy in patients with Khorana scores ≥3 may lead to the highest cost-benefit ratio.

Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score.

Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with multiple myeloma (MM). The International Myeloma Working Group (IMWG) developed guidelines recommending primary thromboprophylaxis, in those identified at high-risk of VTE by the presence of risk factors. The National Comprehensive Cancer Network (NCCN) has adopted these guidelines; however, they lack validation. We sought to develop and validate a risk prediction score for VTE in MM and to evaluate the performance of the current IMWG/NCCN guidelines. Using 4446 patients within the Veterans Administration Central Cancer Registry, we used time-to-event analyses to develop a risk score for VTE in patients with newly diagnosed MM starting chemotherapy. We externally validated the score using the Surveillance, Epidemiology, End Results (SEER)-Medicare database (N = 4256). After identifying independent predictors of VTE, we combined the variables to develop the IMPEDE VTE score (Immunomodulatory agent; Body Mass Index ≥25 kg/m2 ; Pelvic, hip or femur fracture; Erythropoietin stimulating agent; Dexamethasone/Doxorubicin; Asian Ethnicity/Race; VTE history; Tunneled line/central venous catheter; Existing thromboprophylaxis). The score showed satisfactory discrimination in the derivation cohort, c-statistic = 0.66. Risk of VTE significantly increased as score increased (hazard ratio 1.20, P = <.0001). Within the external validation cohort, IMPEDE VTE had a c-statistic of 0.64. For comparison, when evaluating the performance of the IMWG/NCCN guidelines, the c-statistic was 0.55. In summary, the IMPEDE VTE score outperformed the current IMWG/NCCN guidelines and could be considered as the new standard risk stratification for VTE in MM.

External validation of three risk stratification rules in patients presenting with pulmonary embolism and cancer.

Numerous risk stratification rules exist to predict post-pulmonary embolism (PE) mortality; however, few were designed for use in cancer patients. In the EPIPHANY registry, adapted versions of common rules (the Hestia criteria, Pulmonary Embolism Severity Index [PESI], and simplified PESI [sPESI]) displayed high sensitivity for prognosticating mortality in PE patients with cancer. These adapted rules have yet to be externally validated. Therefore, we sought to evaluate the performance of an adapted Hestia criteria, PESI, and sPESI for predicting 30-day post-PE mortality in patients with cancer. We identified consecutive, adults presenting with objectively confirmed PE and cancer to our institution (November 2010 to January 2014). The proportion of patients categorized as low or high risk by these three risk stratification rules was calculated, and each rule's accuracy for predicting 30-day all-cause mortality was determined. Of the 124 patients with PE and active cancer identified, 25 (20%) experienced mortality at 30 days. The adapted Hestia criteria categorized 23 (19%) patients as low risk, while exhibiting a sensitivity of 88% (95% confidence interval [CI] = 68-97%), a negative predictive value NPV of 87% (95% CI = 65-97%), and a specificity of 20% (95% CI = 13-30%). A total of 38 (31%) and 30 (24%) patients were low risk by the adapted PESI and sPESI, with both displaying sensitivities of 92% and NPVs > 93%. Specificities were 36% (95% CI = 27-47%) and 28% (95% CI = 20-38%) for PESI and sPESI. In our external validation, the adapted Hestia, PESI, and sPESI demonstrated high sensitivity but low specificity for 30-day PE mortality in patients with cancer. Larger, prospective trials are needed to optimize strategies for risk stratification in this population.

Predictors of Venous Thromboembolism and Early Mortality in Lung Cancer: Results from a Global Prospective Study (CANTARISK).

BACKGROUND: Patients with lung cancer are known to be at increased risk for venous thromboembolism (VTE). Venous thromboembolism is associated with increased risk for early mortality. However, there have been no studies performing a comprehensive assessment of risk factors for VTE or early mortality in lung cancer patients undergoing systemic chemotherapy in a global real-world setting. MATERIALS AND METHODS: CANTARISK is a prospective, global, noninterventional cohort study including patients with lung cancer initiating a new cancer therapy. Clinical data were collected until 6-month follow-up. The impact of patient-, disease-, and treatment-related factors on the occurrence of VTE and early mortality was evaluated in univariable and multivariable Cox regression analyses. A previously validated VTE risk score (VTE-RS) was also calculated (also known as Khorana score). RESULTS: Of 1,980 patients with lung cancer who were enrolled from 2011 to 2012, 84% had non-small cell lung cancer. During the first 6 months, 121 patients developed a VTE (6.1%), of which 47% had pulmonary embolism, 46% deep vein thrombosis, 3% catheter-associated thrombosis, and 4% visceral thrombosis. Independent predictors for VTE included female sex, North America location, leg immobilization, and presence of a central venous catheter. The VTE-RS was not significantly associated with VTE in either univariable or multivariable analysis in this population. During the study period, 472 patients died, representing 20%, 24%, 36%, and 25% with VTE-RS 1, 2, ≥3, or unknown, respectively (p < .0001). Significant independent predictors of early mortality include older age, current/former smoking, chronic obstructive pulmonary disease, Eastern Cooperative Oncology Group performance status ≥2, no prior surgery, and metastatic disease, as well as the VTE-RS. CONCLUSION: In this global, prospective, real-world analysis, several demographic, geographic, and clinical factors are independent risk factors for VTE and early mortality in patients with lung cancer. The VTE-RS represents a significant independent predictor of early mortality but not for VTE in lung cancer in the era of targeted therapy. IMPLICATIONS FOR PRACTICE: Multiple risk factors for both venous thromboembolism (VTE) and early mortality in patients with lung cancer receiving systemic chemotherapy should guide best practice by better informing clinical evaluation and treatment decision-making. The Khorana risk score is of value in assessing the risk of early all-cause mortality along with other clinical parameters in patients with lung cancer receiving systemic therapy. Further study is needed to fully evaluate the validity of the risk score in predicting the risk of VTE in the modern era of lung cancer therapy.