ALBERT

Description: Background: Cancer is associated with thrombosis, but the frequency of thromboembolism in hospitalized cancer patients receiving contemporary chemotherapy regimens is not known. We investigated the frequency of arterial and venous thromboembolism in hospitalized cancer patients receiving active therapy (as identified by the presence of neutropenia) and characterized its association with in-hospital mortality. Methods: We conducted a retrospective cohort study using the discharge database of the University HealthSystem Consortium. This included 66,106 adult neutropenic cancer patients with 88,074 hospitalizations between 1995 and 2002 at 115 academic medical centers. Patients were identified using ICD-9-CM codes that contained at least one diagnosis of malignant disease and agranulocytosis. Patients with thromboembolism were identified using codes for venous thrombosis, pulmonary embolism, arterial embolism, acute cerebrovascular disease, and acute coronary arterial disease. The association of VTE with clinical variables was studied in univariate analysis and in a multivariate logistic regression model. The chi-square test was used to compare categorical variables, and Cochran-Armitage test to determine trend. Results: Thromboembolism was reported in 5,272 patients (8%), with 5.4% patients developing venous and 1.5% arterial thromboembolism during the first hospitalization. There was a significant association between the occurrence of venous and arterial thromboembolism (OR 1.73, 95%CI, 1.38–2.16). Venous thromboembolism was more frequent in patients with metastatic disease (OR, 1.23, 95% CI 1.13–1.34), but arterial thromboembolism was not (OR, 0.59, 95% CI, 0.51–0.69). In-hospital mortality was significantly greater in patients with venous (OR 2.01, 95% CI 1.83– 2.22) or arterial thromboembolism (OR 5.04, 95% CI, 4.38–5.79), even in patients without metastatic disease. Patients with lymphoma or leukemia accounted for one-third of venous events and one-half of arterial events. Clinical variables most frequently associated with thromboembolism in a multivariate logistic regression analysis were age ≥ 65 years, primary sites of cancer including lung, gastrointestinal, gynecologic and brain, length of stay ≥ 10 days, and comorbidities including infection, pulmonary and renal disease, and obesity. From 1995 to 2002, there was a 36% increase in venous and a 124 % increase in arterial events (P for trend

Description: Background: Venous Thromboembolism (VTE) is a common complication of cancer and is strongly associated with early all-cause mortality during the course of cancer chemotherapy (Kuderer et al. ASCO 2008). A clinical model for predicting the risk of VTE in cancer patients initiating chemotherapy has been recently developed and validated (Khorana et al. Blood 2008). Risk of VTE in low (group I), intermediate (group II) and high risk patients (group III) was 0.8%, 1.8% and 7.1%, respectively. The aim of current study is to evaluate the ability of the VTE risk model to predict disease progression and early all-cause mortality. Methods: A prospective study of 4,458 adult cancer patients with solid tumors or malignant lymphoma initiating a new chemotherapy regimen was conducted between 2002 and 2006 at 115 randomly selected practice sites throughout the USA. Demographic, clinical and treatment-related information was captured prospectively at baseline and during the first four cycles of chemotherapy, including rates of documented VTE, disease recurrence and deaths from all causes. Progression-free survival (PFS) and overall survival (OS) within 4 months of starting chemotherapy were estimated by the method of Kaplan-Meier and adjusted hazard ratios (HR ± 95% CI) were estimated by a Cox regression model, incorporating VTE as a time-dependent covariate. Results: Patient age ranged from 18–97 with a mean of 60 years. VTE occurred in 3% of patients by 4 months with a median of 38 days following initiation of chemotherapy. The HR for VTE occurrence among risk score groups II and III, compared to group I, were 3.07 [1.39–6.77] and 11.73 [5.22–16.37], (P

Description: Introduction: Neutropenic complications including severe neutropenia (SN) and febrile neutropenia (FN) represent major dose-limiting toxicities of cancer chemotherapy. A prospective study was undertaken to develop and validate a predictive model for neutropenic events in patients receiving cancer chemotherapy. The final risk model based on mature data is presented. Methods: Between 2002 and 2006, 4458 consenting patients starting a new chemotherapy regimen at 115 randomly selected community oncology practices throughout the United States were enrolled including 3760 with cancers of breast, lung, colorectum, ovary and malignant lymphoma receiving at least one cycle of treatment. Using a 2:1 random split sample methodlogy, a risk model for first-cycle SN or FN was derived and validated based on multivariate logistic regression analysis incorporating pretreatment variable information. The cumulative risk of events over the initial 120 days of treatment was estimated by the method of Kaplan and Meier. High and low risk groups were defined on the basis of the median predicted risk and model test performance characteristics were estimated. Results: Following adjustment for cancer type, important predictive factors included: older age, prior chemotherapy, abnormal hepatic or renal function, low pretreatment white blood count, immunosuppressive medications and planned relative dose intensity 〉85% as well as use of several specific chemotherapeutic agents including anthracyclines, taxanes, alkylating agents, topoisomerase inhibitors, gemcitabine or vinorelbine. Lower risk of neutropenic complications were associated with primary prophylaxis with a colony-stimulating factor (CSF). Individual risk estimates based on the model ranged from 0–89% with mean and median of 19.2% and 10.1%, respectively. The model was associated with an R2 of 0.34 and demonstrated excellent discrimination with a c-statistic of 0.833 [95% CI: 0.813–0.852, P

Description: Anemia represents the most common hematological toxicity in cancer patients receiving systemic chemotherapy and is associated with considerable morbidity and cost. Current guidelines for chemotherapy-induced anemia call for intervention at a hemoglobin

Description: Background: Thromboembolism (TE) is a common complication of hospitalized non-transplant cancer patients. To date, the extent and impact of TE in stem cell transplant patients is unknown, in part because it is considered a low risk group given the high prevalence of thrombocytopenia. The purpose of this study is to evaluate the incidence of and risk factors for TE in cancer patients undergoing stem cell transplantation. Methods: We conducted a retrospective analysis of all discharge summaries from the 115 US academic health centers reporting to the University HealthSystem Consortium from 1995 to 2002. We identified a total of 7,087 patients with hematologic malignancies undergoing allogeneic and autologous stem cell transplantation. The incidence of and risk factors for venous and arterial TE was analyzed in univariate and multivariate logistic regression analysis with adjusted odds ratios as estimates of relative risk. Results: TE was reported in 389 (5.5%) transplant patients with 4.8% patients developing venous and 0.7% arterial TE. The incidence of TE was greater in allogeneic (6.8%) compared to autologous (4.8%) transplant patients (p

Description: Background: Retrospective studies have reported inconsistent results concerning risk of acute myeloid leukemia or myelodysplastic syndrome (t-ML) in cancer patients receiving granulocyte colony-stimulating factor (G-CSF) along with systemic chemotherapy. In order to further evaluate any potential impact of chemotherapy with G-CSF support on overall survival (OS) and risk of t-ML in malignant lymphoma, a systematic review and subsequent meta-analysis of prospective, randomized controlled clinical trials were conducted. Methods: Electronic databases including Medline, EMBASE, BIOSIS and the Cochrane Library were searched through August 2008 identifying 5885 articles for initial screening. Eligibility criteria included studies of adult patients with non-myeloid malignancies receiving chemotherapy (CT) with or without G-CSF with at least 2 years of follow-up. Of the 136 potentially eligible publications identified, 8 were from prospective, randomized, controlled trials (RCTs) in adult patients with non-Hodgkin’s lymphoma (7) or Hodgkin’s disease (1). Excluded reports consisted of retrospective studies, duplicate reports, studies with no control group or studies involving stem cell transplantation. Study outcomes included all secondary malignancies, t-ML, OS and delivered chemotherapy dose intensity. Meta-analyses were based on the method of Mantel and Haenszel with summary estimates and 95% CIs for both relative risk (RR) and absolute risk difference (ARD;%). Results: In 8 RCTs, a total of 4089 patients were randomized to receive CT with G-CSF support (n=2032) versus no G-CSF (n=2057). In 5 of the 8 trials, dose intensified or dose dense CT was given in the G-CSF arms compared to standard CT without initial G-CSF. Initial CT dose and schedule were the same in the remaining 3 trials although each reported significantly greater overall delivered dose intensity in the G-CSF arm. No signficant heterogeneity was observed for the primary outcomes. Among 6 reporting RCTs, secondary malignancies occurred in 36 patients in the G-CSF arms versus 35 patients in control arms. T-ML was reported in 15 patients randomized to G-CSF compared to 6 in control patients [RR=2.30; 0.95–5.58; ARD = 0.6%; −0.1%–1.3%; p=.06]. In all 8 studies, patients receiving G-CSF received significantly greater chemotherapy dose intensity compared to controls. Among patients randomized to G-CSF support, a statistically significant increase in OS [RR=0.87; 0.81–0.94; ARD = −5.0%; −7.7%–−2.3%; p

Description: Introduction: Although 60% of all malignancies occur in patients ≥65, this population is poorly represented in cancer clinical trials. While fit elderly patients appear to tolerate chemotherapy as well as younger individuals, less is known about chemotherapy tolerance in older cancer patients with poor performance status or co-morbidities. The purpose of this study was to examine the impact of patient and disease characteristics on the reported toxicities of cancer chemotherapy. Methods: This study represents part of a prospective, nationwide registry based at 137 randomly selected practice sites throughout the US. The major malignancies considered were cancers of the breast (33%), colon (10%), lung (19%) and ovary (7%) along with malignant lymphoma (8%). To date, 3422 patients have been registered of which 2719 are available for analysis including 1083 patients age ≥65 (40%). Primary outcome measures were: relative dose intensity (RDI) compared to standard doses, anemia (Hgb

Description: Background: Venous thromboembolism (VTE) is a significant complication of cancer and particularly of newer anti-cancer therapies. The risk of VTE is estimated to be 0.04%/month (0.5%/year) in cancer patients. We conducted a prospective analysis to determine the frequency and risk factors for symptomatic VTE in cancer patients actively receiving chemotherapy. Methods: The Awareness of Neutropenia in Cancer (ANC) Study Group is currently enrolling patients with breast, lung, colon, ovary and other cancers, at 137 sites nationwide, with an accrual goal of 4,500 patients. Patients are registered at the time of initiation of a new chemotherapy regimen, and followed for the duration of 4 cycles. The association of VTE with clinical variables was studied in univariate analysis and in a multiple logistic regression model. No significant first-order interactions were observed between the variables in this model. A risk score for VTE was estimated for each subject from the weighted sum of model predictor variables from the multivariate model. Results: A total of 2,151 patients treated with at least one cycle of chemotherapy were available for analysis. Pulmonary embolism occurred in 11, and deep venous thrombosis in 35, for a VTE incidence of 2.14 % over median follow-up of 2.5 months (0.85%/month). Incidence of first VTE event was greatest in cycles 1 (0.93%/cycle) and 2 (0.88%/cycle), and declined in cycle 3 (0.53%/cycle). Incidence varied significantly by site of disease (p=0.01) with highest rates in patients with upper gastrointestinal (2.4%/month) and lung cancers (1.2%/month), and lymphomas (1.2%/month). Other clinical variables associated with development of VTE in univariate analysis included baseline platelet count ≥350,000, an ECOG PS ≥ 2, and baseline use of erythropoietin or colony-stimulating factors. Patients with VTE reported a chemotherapy delay of ≥ 7 days in 40% compared to 23.6% in patients without VTE (OR 2.15, p=0.01). Based on the results of the multivariate model (c statistic=0.73[.65,.81]) the population was divided into low, intermediate and high-risk based on tertiles of risk scores. Patients deemed high-risk had a VTE risk of 1.5%/month, which was a six-fold increase compared to those deemed low-risk (see Table). Conclusion: Symptomatic VTE is much more frequent in cancer patients on chemotherapy than previously estimated, even in patients with hematologic malignancies. VTE is associated with a nearly two-fold risk of significant delay in chemotherapy, which could impact on cancer outcomes. This is the first prospectively generated predictive model for chemotherapy-associated thrombosis, and can be used to define a high-risk study population for trials of thromboprophylaxis. Incidence of Chemotherapy-Associated VTE By Risk Categories Risk Score N VTE events Observed VTE Incidence(%) Predicted VTE Incidence(%) Low 648 4 0.62(0.24/month) 0.58(0.23/month) Intermediate 702 10 1.42(0.56/month) 1.48(0.59/month) High 799 30 3.75(1.5/month) 3.73(1.49/month)

Description: Background: Chemotherapy-induced neutropenia is frequently associated with neutropenic complications resulting in reduced relative dose intensity (RDI) potentially compromising clinical outcomes. Retrospective analyses have identified several factors but are limited by variable reporting and missing data. Methods: Results from an ongoing prospective study of cancer chemotherapy patients based at more than 100 randomly selected US centers are reported. Demographic, clinical and treatment-related variables were obtained on 345 patients with malignant lymphoma (ML). Data are presented on the first 265 patients completing at least one cycle of chemotherapy. Planned and unplanned reductions in relative dose intensity (RDI) were estimated along with the risk of neutropenia and febrile neutropenia (FN) over the first four cycles of treatment are presented. Results: Patients with Hodgkin’s disease (HD; N=43) received five different regimens including ABVD (84%) while patients with Non-Hodgkin’s lymphoma (NHL; N=222) received 33 different regimens the most common of which was CHOP (53%). Neutrophil nadirs

Description: Background While ambulatory patients receiving cancer chemotherapy are at increased risk for venous thromboembolism (VTE), current guidelines do not recommend routine thromboprophylaxis with a few notable exceptions (Lyman, Khorana et al, J Clin Oncol 2013). A previously validated VTE risk score for cancer outpatients stratifies patients into low (0), intermediate (1-2), or high (〉=3) risk categories (Khorana, Kuderer et al, Blood 2008). Understanding cancer types at greatest risk for VTE as well as early mortality and progression based on the risk score provides key clinical understanding. Methods A prospective cohort study was conducted of consenting solid tumor and lymphoma patients initiating a new chemotherapy regimen at 115 randomly selected US oncology practices between 2002 – 2006 by the ANC Study Group. VTE incidence, progression-free survival (PFS), and all-cause mortality over the first 120 days (early mortality) of ambulatory chemotherapy were estimated based on the method of Kaplan and Meier. Results Among 4,458 patients initiating a new chemotherapy regimen, 93 (2.1%) developed a symptomatic VTE within 120 days of chemotherapy. The risk of VTE across cancer types increased from 0.6%, to 1.8% to 6.6% in low-, intermediate- and high-risk categories, respectively. The risk of VTE among low risk patients was 1% or less across all cancer types. However, the risk of VTE was highest among intermediate- and high-risk categories in patients with breast, colorectal, and lung cancer, reaching 16% for high risk breast cancer patients. Early all-cause mortality occurred in 136 patients (3.1%) and also increased with increasing risk score from 0.8% to 3.4% to 6.4% in low-, intermediate- and high-risk categories, respectively. The risk of early mortality was 2.1% or less in low risk patients across all cancer types. However, the risk of early mortality was highest among high-risk category patients, reaching 23% and 14% in colorectal cancer patients and pancreatic or gastric cancer patients, respectively. PFS decreased from 92% to 82% to 72% across the three risk categories, with lowest rates of PFS among colorectal (52%) and lung cancer (52%) patients. Conclusions VTE incidence and all-cause mortality increase and PFS correspondingly decreases with increasing VTE risk score across major solid tumors. Interestingly, while breast cancer is not considered a high risk tumor for VTE, breast cancer patients with a risk score of 〉=3 had the highest VTE incidence compared to other major solid tumor types. Among patients with a risk score of 〉=3, gastrointestinal cancer patients had the greatest risk of early mortality and correspondingly, the lowest PFS compared to other major solid tumors. These findings also suggest that both the mortality risk as well as the VTE risk are only partially influenced by tumor type. Funding: 1KM1-CA156687-01 (NK), ASCO Young Investigator Award (NK), NHLBI-1R01HL095109 (all), ANC Study Group (GL), and K23 CA120587 (AK). Disclosures: No relevant conflicts of interest to declare.