Kristen M. Sanfilippo

Hypertension and obesity and the risk of kidney cancer in 2 large cohorts of US men and women

Kidney cancer incidence is increasing globally. Reasons for this rise are unclear but could relate to obesity and hypertension. We analyzed longitudinal relationships between hypertension and obesity and kidney cancer incidence in 156 774 participants of the Women’s Health Initiative clinical trials and observational studies over 10.8 years. In addition, we examined the effect of blood pressure (BP) on kidney cancer deaths for over 25 years among the 353 340 men screened for the Multiple Risk Factor Intervention Trial (MRFIT). In the Women’s Health Initiative, systolic BP (SBP) was categorized in 6 groups from <120 to >160 mm Hg, and body mass index was categorized using standard criteria. In age-adjusted analyses, kidney cancer risk increased across SBP categories (P value for trend <0.0001) and body mass index categories (P value for trend <0.0001). In adjusted Cox proportional hazards models, both SBP levels and body mass index were predictors of kidney cancer. In the MRFIT sample, there were 906 deaths after an average of 25 years of follow-up attributed to kidney cancer among the 353 340 participants aged 35 to 57 years at screening. The risk of death from kidney cancer increased in a dose–response fashion with increasing SBP (hazard ratio, 1.87 for SBP>160 versus <120 mm Hg; 95% confidence interval, 1.38–2.53). Risk was increased among cigarette smokers. Further research is needed to determine the pathophysiologic basis of relationships between both higher BP and the risk of kidney cancer, and whether specific drug therapies for hypertension can reduce kidney cancer risk.

Waldenström macroglobulinemia: a Surveillance, Epidemiology, and End Results database review from 1988 to 2005

Little information is present on the incidence and survival of Waldenstr o m macroglobulinemia (WM). Th e last published study to examine the epidemiological characteristics of WM used Surveillance, Epidemiology, and End Results (SEER) data from 1988 to 1994 [1]. Th e study had a limited scope, only examining the incidence patterns of WM in various demographics over a 6-year time period, and compared these data to the incidence of other lymphoproliferative disorders. Because of the short time period included, the population database was small and survival trends could not be discerned. Our aim was to examine the incidence and survival patterns of WM among various demographic groups and to evaluate changes in patterns during an extended time period. We searched the April 2008 release of the SEER-17 registry data, version 6.4.4, for patients aged 21 years or older with WM as defi ned by the International Classifi cation of Diseases for Oncology (ICD-O-3) code 9761 [2]. Between the years 1988 and 2005, we identifi ed 2696 cases of WM. Patients diagnosed by death certifi cate or autopsy only were excluded from the study. A Cox proportional hazards model was used to estimate overall survival (OS) functions based on age and year of diagnosis. A statistically signifi cant diff erence was testifi ed by a p -value of 0.05 from the Wald χ 2 test. Hazard of death was then determined for any 5-year increase of time of diagnosis based on age at diagnosis. Of the 2696 cases of WM meeting our inclusion criteria, 1659 were males and 1037 were females (incidence ratio of 1.6:1). Th e incidence of reported cases was stable from 1988 to 2005 at 0.3 per 100 000 persons. Th e median age at diagnosis was 73 (range 23 – 98) years, with 1603 patients aged 70 years or older and 1093 younger than 70 years. Survival data for the various subgroups are summarized in Table I. Median OS for the entire cohort was 65 months (95% confi dence interval [CI], 61 – 69) with a 5-year OS of 52% (95% CI, 50 – 55%). Th ere was a signifi cant diff erence in survival for individuals aged 70 years versus those aged 70 years, with age-adjusted 5-year OS of 71% (95% CI, 68 – 74%) and 39% (95% CI, 36 – 42%), respectively ( p 0.0001) and ageadjusted median OS of 107 months (95% CI, 94 – 122) for individuals 70 and 48 months (95% CI, 43 – 51) for those 70 ( p 0.0001). Gender and race had no impact on OS ( p 0.23 and 0.13, respectively). When assessed by date of diagnosis (1988 – 2005), there was an overall decreased risk of death. Table II depicts overall and age-stratifi ed hazard ratio (HR) of death based on year of diagnosis from 1988 to 2005. Year of diagnosis was assessed in 5-year increments. An overall HR of 0.90 (95% CI, 0.84 – 0.96) was found for the entire population. Th is depicts a 10% decrease in hazard of death for each 5-year increase in year of diagnosis. Looking at the HR for age at diagnosis, this benefi t is most pronounced in younger individuals, with those diagnosed at age 50 having a 30% decrease in hazard of death for each 5-year increase in year of diagnosis over the study period 1988 – 2005. Patients aged 75 and older had no signifi cant improvement in hazard of death over the study period. Th e impact of age in our analysis is consistent with previously reported studies [3,4]. Th e fi nding in our report that the period of diagnosis appears to be associated with improvement in OS seems to support the fi ndings of Kristinsson et al ., who studied 1555 patients diagnosed from 1980 to 2005 in

Improving accuracy of International Classification of Diseases codes for venous thromboembolism in administrative data

BACKGROUND Increasingly, clinicians and researchers are using administrative data for clinical and outcomes research. However, they continue to question the accuracy of using International Classification of Diseases 9th Revision (ICD-9) codes alone to capture diagnoses, especially venous thromboembolism (VTE), in administrative data. OBJECTIVES We tested the hypothesis that incorporation of treatment data and/or common procedural terminology (CPT) codes could improve accuracy of administrative data in detecting VTE. Research Design Using the Veterans Affairs Central Cancer Registry, we compared three competing algorithms by performing three cross-sectional studies. Algorithm 1 identified patients by ICD-9 codes alone. Algorithm 2 required VTE treatment in addition to ICD-9 codes. Algorithm 3 required a VTE diagnostic CPT code in addition to treatment and ICD-9 criteria. RESULTS The accuracy of ICD-9 codes alone for detection of VTE was marginal, with a PPV of 72%. The PPV was improved to 91% after addition of treatment data (algorithm 2). As compared to algorithm 2, addition of CPT codes (algorithm 3) did not significantly increase the accuracy of detecting VTE (PPV 92%), but decreased sensitivity from 72% to 67%. CONCLUSIONS Accuracy of VTE detection significantly improved with addition of treatment data to ICD-9 codes. This approach should facilitate use of administrative data to assess the incidence, epidemiology, and outcomes of VTE.

Comparative effectiveness of anthracycline-containing chemotherapy in United States veterans age 80 and older with diffuse large B-cell lymphoma

OBJECTIVES While anthracycline-based treatment can cure diffuse large B-cell lymphoma, most patients over age 80 do not receive doxorubicin due to toxicity concerns. This study evaluated this practice, as patients age 80 and older are largely excluded from clinical trials. The primary outcome of interest was overall survival. Secondary outcomes included treatment-related mortality and anthracycline dose intensity. MATERIALS AND METHODS We assembled a cohort of 530 newly diagnosed diffuse large B-cell lymphoma patients age 80 or older diagnosed within United States Veterans Health Administration. Treatment and survival information were obtained to determine associations between anthracycline use, dose intensity, treatment-related mortality and overall survival. RESULTS Of the 530 patients, 285 received systemic treatment and 193 received an anthracycline. After controlling for potential confounders, rituximab decreased mortality (hazard ratio, 0.62; 95% confidence interval [CI]: 0.44-0.88), while doxorubicin was not significantly associated with mortality (hazard ratio, 0.87; 95% CI: 0.64-1.17). Completion of treatment with anthracycline dose intensity ≥85% of expected was only 14%. Patients treated with anthracycline dose intensity <85% had better one year survival compared to those treated at ≥85% (70% vs. 59%, p=0.029). CONCLUSION These results suggest that full dose anthracycline therapy may be less important in the treatment of diffuse large B-cell lymphoma patients over age 80. The low frequency of completion of full dose intensity treatment suggests that standard doses are an unrealistic standard of care for patients this age. Alternate treatment strategies and risk stratification should be considered for these patients.

Influence of Body Mass Index on Survival in Veterans With Multiple Myeloma

PURPOSE We investigated the association between body mass index (BMI) at the time of multiple myeloma (MM) diagnosis and overall survival in a cohort of patients within the Veterans Health Administration system. We also evaluated the association between weight loss in the year prior to diagnosis and survival. PATIENTS AND METHODS Prospective analysis was performed on a retrospectively assembled cohort of 2,968 U.S. veterans diagnosed and treated for MM between September 1, 1999, and September 30, 2009, with follow-up information through October 22, 2011. Cox modeling controlling for patient- and disease-related prognostic variables was used to analyze the data. RESULTS Underweight patients (BMI <18.5 kg/m2) had increased mortality, whereas patients who were overweight (BMI 25-29.9 kg/m2) and obese (BMI ≥30 kg/m2) had lower mortality compared with healthy-weight patients (BMI 18.5-24.9 kg/m2). Weight loss ≥10% of baseline in the year before diagnosis was also associated with increased mortality and made the association between increased BMI and survival nonsignificant. CONCLUSION Disease-related weight loss may be an important and heretofore unknown indicator of poor prognosis in MM. Assessment of weight loss prior to MM diagnosis should become a standard component of the clinical history in patients with newly diagnosed MM. Further research may identify relationships between disease-related weight loss and currently used prognostic factors in MM, further defining the role of this clinical factor in prognostic stratification.

Comparative Effectiveness on Survival of Zoledronic Acid versus Pamidronate in Multiple Myeloma

Abstract Zoledronic acid and pamidronate are the two bisphosphonates approved in the United States to reduce multiple myeloma skeletal complications. Little prior evidence exists comparing survival outcomes between the two. We evaluated the incidence of skeletal-related events and overall survival in patients with myeloma treated with zoledronic acid versus pamidronate using a cohort of 1018 United States veterans. At a median follow-up of 26.9 months, patients receiving zoledronic acid had a 22% reduction in risk of death compared to pamidronate (hazard ratio 0.78; 95% confidence interval, 0.67–0.92). The benefit persisted after controlling for potential confounders. Adjusted Cox modeling with inverse probability weighting and propensity score matching supported these findings. Zoledronic acid was also associated with a 25% decrease in skeletal-related events. Zoledronic acid is associated with increased overall survival and decreased skeletal-related events compared to pamidronate in patients with multiple myeloma and should become the preferred bisphosphonate.

Statins Are Associated With Reduced Mortality in Multiple Myeloma

Purpose The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) have activity in one of the pathways influenced by nitrogen-containing bisphosphonates, which are associated with improved survival in multiple myeloma (MM). To understand the benefit of statins in MM, we evaluated the association between statin use and mortality in a large cohort of patients with MM. Patients and Methods From the Veterans Administration Central Cancer Registry, we identified patients diagnosed with MM between 1999 and 2013. We defined statin use as the presence of any prescription for a statin within 3 months before or any time after MM diagnosis. Cox proportional hazards regression assessed the association of statin use with mortality, while controlling for known MM prognostic factors. Results We identified a cohort of 4,957 patients, of whom 2,294 received statin therapy. Statin use was associated with a 21% decrease in all-cause mortality (adjusted hazard ratio, 0.79; 95% CI, 0.73 to 0.86; P < .001) as well as a 24% decrease in MM-specific mortality (adjusted hazard ratio, 0.76; 95% CI, 0.67 to 0.86; P < .001). This association remained significant across all sensitivity analyses. In addition to reductions in mortality, statin use was associated with a 31% decreased risk of developing a skeletal-related event. Conclusion In this cohort study of US veterans with MM, statin therapy was associated with a reduced risk of both all-cause and MM-specific mortality. Our findings suggest a potential role for statin therapy in patients with MM. The putative benefit of statin therapy in MM should be corroborated in prospective studies.

Impact of body mass index on incidence of febrile neutropenia and treatment-related mortality in United States veterans with diffuse large B-cell lymphoma receiving rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone.

In 2012, guidelines from the American Society of Clinical Oncology (ASCO) summarized the literature on chemotherapy dosing based upon actual body weight versus ideal or adjusted body weight. Their conclusion, largely drawn from studies of solid tumor patients, was that chemotherapy administration based upon actual body weight did not increase short-term toxicities. This resulted in the recommendation against the use of empiric dose-reduction solely due to obesity status (Griggs et al, 2012). To better understand if this recommendation could be applied to patients with diffuse large B-cell lymphoma (DLBCL), we examined the associations between body mass index (BMI) and relative dose-intensity with the outcomes of febrile neutropenia and treatment-related mortality in a large cohort of DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). We identified a retrospective cohort of patients with DLBCL within the United States Veterans Health Administration (VHA) using previously published methods and inclusion and exclusion criteria (Carson et al, 2012). Details of chemotherapy, radiotherapy, supportive care medications, and hospitalizations were determined through chart abstraction. Weight and height measurements within one month of treatment initiation were used to calculate BMI and body surface area (BSA). Patients were categorized as underweight, normal-weight, overweight, or obese in accordance with the WHO classification. The Romano comorbidity index was calculated using ICD-9 codes (Romano et al, 1993). Average relative dose-intensity was calculated utilizing methods previously published (Lyman et al, 2004). The expected number of chemotherapy cycles was 3 in stage I/II patients receiving radiotherapy and 6 in all other patients. Chemotherapy doses <85% of expected in the first cycle were considered “dose-reduced”. Febrile neutropenia was determined by chart abstraction, and was considered present based upon review of electronic medical records. Treatment-related mortality was defined as death within 30 days of last chemotherapy administration. Logistic regression evaluated variables associated with treatment-related mortality in the overall cohort and then among those without first cycle dose-reductions. Missing data on LDH, stage, and B-symptoms were handled through use of multiple imputation (Sterne et al, 2009). All statistical analyses were performed using SAS version 9.2 (SAS Institute, Cary, NC). All p-values reported are 2-tailed and p-values <0.05 were considered significant. We identified a total cohort of 1,241 DLBCL patients who received R-CHOP within the VHA system. Univariate comparisons stratified by BMI are presented in Table I. There were no significant differences in the average relative dose-intensities or levels of G-CSF support among the BMI groups. Obese patients were not significantly more likely to undergo first cycle dose-reduction. The incidence of febrile neutropenia and treatment-related mortality among the three groups differed significantly, with obese patients experiencing less of both. Across all treatment cycles, obese patients were significantly less likely to experience febrile neutropenia (obese: 17.8%, overweight: 23.0%, normal-weight: 28.9%, age-adjusted p<0.001). Obese patients were also significantly less likely to experience treatment-related mortality (obese: 5.5%, overweight: 8.1%, normal-weight: 11.3%, age-adjusted p=0.017). Table I Demographic Characteristics, Dose Characteristics, and Toxicity Outcomes of United States Veterans with DLBCL Treated with R-CHOP within VHA System by BMI Group (n=1,241). In multivariate logistic regression controlling for age, stage, LDH at diagnosis, B-symptoms, comorbidity score, and G-CSF use, obesity was associated with decreased treatment-related mortality compared to normal-weight patients (OR 0.50; 95% CI 0.28–0.90). Overweight patients demonstrated a non-significant trend towards reduced treatment-related mortality (OR 0.73; 95% CI 0.46–1.14). Among patients without first cycle dose-reductions, obesity was still associated with decreased treatment-related mortality (OR 0.46; 95% CI 0.24–0.90), and overweight patients demonstrated a non-significant trend towards reduced treatment-related mortality (OR 0.69; 95% CI 0.42–1.14) (Table II). Table II Multivariate Odds Ratios1 for Treatment-Related Mortality. Consistent with the ASCO guidelines, we found no evidence that treatment of overweight and obese DLBCL patients with actual body weight chemotherapy doses increased the incidence of febrile neutropenia or treatment-related mortality. In fact, we observed a significantly decreased incidence of febrile neutropenia among obese patients despite similar average relative dose-intensities and G-CSF support. Furthermore, obesity was associated with decreased treatment-related mortality after controlling for age, G-CSF use, and other prognostic factors. This relationship held among patients who received >85% of expected doses in the first treatment cycle, suggesting that fears of excess febrile neutropenia and treatment-related mortality among obese patients are unfounded in this population. This is of particular importance in DLBCL as studies have suggested that achieving average relative dose-intensity >90% is associated with improved long-term outcomes (Bosly et al, 2008). The ASCO guidelines also raised the question of whether dose-reductions might compromise efficacy in obese patients. Evidence suggests improved overall survival among patients experiencing neutropenia or leukopenia during chemotherapy (Shitara et al, 2011). Due to the confounding by indication that is inherent in observational studies, we were unable to fully answer this question (Jepsen et al, 2004). While a trial randomizing obese patients to R-CHOP doses based upon actual vs. ideal body weight would provide a clear answer, it is unlikely that such a study will ever be performed. The strengths and limitations of this study should be highlighted. Since, the VHA is the largest integrated health system in the United States, we were able to assemble a large patient cohort with detailed patient information. However, consistent with the historic military demographics, this cohort was almost entirely men, which may limit the applicability of our findings. An additional limitation of our study is that we could not quantify differences in long-term toxicities among BMI groups. Doxorubicin is known to cause a significant, dose-dependent incidence of heart failure (Gharib & Burnett, 2002). The effect doxorubicin dosing based upon actual body weight on the incidence of doxorubicin-induced cardiomyopathy remains unknown. Overall, this study supports the application of the ASCO obesity guidelines in overweight and obese DLBCL patients. Specifically, we found no evidence that treatment with full weight-based therapy in overweight or obese patients increases the risk of febrile neutropenia or treatment-related mortality. Until data emerges suggesting otherwise, in the absence of other contraindications, oncologists treating overweight and obese DLBCL patients with R-CHOP should use actual body weight in dosing calculations.

Incidence of venous thromboembolism in patients with non-Hodgkin lymphoma

INTRODUCTION Patients with non-Hodgkin lymphoma (NHL) have an increased risk of venous thromboembolism (VTE). Current risk-prediction models classify NHL as a single entity. We aimed to quantify the difference in VTE risk in follicular lymphoma (FL) versus diffuse large B cell lymphoma (DLBCL). METHODS Using a prospective cohort study, we identified 2730 patients (2037 DLBCL; 693 FL) within the Veterans Administration Central Cancer Registry. A competing risk model assessed the association between VTE risk and histology in the first year after NHL diagnosis. We assessed the effect of additional risk factors for VTE in NHL. RESULTS In univariate analysis, DLBCL was associated with increased risk of VTE compared to FL in the first year after diagnosis; this association was no longer significant in adjusted analysis (adjusted hazard ratio (aHR) 1.52; 95% CI 0.97-2.40). Major risk factors for VTE included history of VTE before NHL diagnosis (aHR 4.73, p≤0.0001) and time period during chemotherapy administration (aHR 7.60, p≤0.0001). Additional risk factors included: stage III/IV disease (p=0.02), BMI≥30 (p=0.02), B-symptoms (p=0.02), and doxorubicin (p=0.04). The cumulative incidence of VTE was highest in the period following diagnosis and decreased over time for both histologies. CONCLUSION DLBCL is associated with increased risk of VTE compared to FL. This risk is markedly attenuated when adjusting for additional risk factors. The strongest predictors for development of VTE included: time period during chemotherapy administration (especially doxorubicin) and history of VTE. This knowledge can assist clinicians in identifying NHL patients at high risk for VTE.

Longitudinal Body Composition Changes in Diffuse Large B-cell Lymphoma Survivors: A Retrospective Cohort Study of United States Veterans

BACKGROUND Body composition parameters are associated with long-term health outcomes. We assessed longitudinal body composition changes in diffuse large B-cell lymphoma (DLBCL) survivors and identified clinical variables associated with the long-term development of sarcopenia and visceral obesity. METHODS A retrospective cohort of United States veterans with DLBCL treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab, was assembled. Muscle, subcutaneous fat, and visceral fat areas were measured with computed tomography analysis. Data were analyzed with repeated-measures analysis of variance and logistic regression. All statistical tests were two-sided. RESULTS Three hundred forty-two patients were included. Muscle area initially decreased during treatment, then returned to baseline by 24 months after treatment. Subcutaneous fat area increased from baseline by 6.5% (95% confidence interval [CI] = 2.6% to 10.5%) during treatment and by 21.4% (95% CI = 15.7% to 27.2%) by 24 months after treatment. Visceral fat area increased from baseline by 4.5% (95% CI = -0.9% to 9.9%) during treatment and by 21.6% (95% CI = 14.8% to 28.4%) by 24 months after treatment. Variables associated with long-term development of sarcopenia included: baseline sarcopenia (adjusted odds ratio [aOR] = 17.21, 95% CI = 8.48 to 34.94), older than age 60 years (aOR = 2.93, 95% CI = 1.46 to 5.88), and weight loss greater than 5% during treatment (aOR = 2.40, 95% CI = 1.12 to 5.14). Variables associated with long-term visceral fat gain included: weight gain greater than 5% during treatment (aOR = 4.60, 95% CI = 2.42 to 8.74). CONCLUSIONS DLBCL survivors undergo unfavorable long-term body composition changes. Patients at risk for the long-term development of sarcopenia or visceral obesity can be identified based on clinical risk factors and targeted for lifestyle interventions.