Suhong Luo

Increased Body Mass Index Is Associated With Improved Survival in United States Veterans With Diffuse Large B-Cell Lymphoma

PURPOSE Obesity increases the risk of death from many malignancies, including non-Hodgkins lymphoma (NHL). In diffuse large B-cell lymphoma (DLBCL), the most common form of NHL, the association between body mass index (BMI) at diagnosis and survival is unclear. PATIENTS AND METHODS We evaluated the association between BMI at diagnosis and overall survival in a retrospective cohort of 2,534 United States veterans diagnosed with DLBCL between October 1, 1998 and December 31, 2008. Cox modeling was used to control for patient- and disease-related prognostic variables. RESULTS Mean age at diagnosis was 68 years (range, 20 to 100 years); 64% of patients were overweight (BMI, 25 to < 30) or obese (BMI, ≥ 30). Obese patients were significantly younger, had significantly fewer B symptoms, and trended toward lower-stage disease, compared with other BMI groups. Cox analysis showed reduced mortality in overweight and obese patients (overweight: hazard ratio [HR], 0.73; 95% CI, 0.65 to 0.83; obese: HR, 0.68; 95% CI, 0.58 to 0.80), compared with normal-weight patients (BMI, 18.5 to < 25). Treatment during the rituximab era reduced the risk of death without affecting the association between BMI and survival. Disease-related weight loss occurred in 29% of patients with weight data 1 year before diagnosis. Cox analysis based on BMI 1 year before diagnosis continued to demonstrate reduced risk of death in overweight and obese patients. CONCLUSION Being overweight or obese at the time of DLBCL diagnosis is associated with improved overall survival. Understanding the mechanisms responsible for this association will require further study.

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.

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.

Association between metformin use and progression of monoclonal gammopathy of undetermined significance to multiple myeloma in US veterans with diabetes mellitus: a population-based retrospective cohort study

BACKGROUND Multiple myeloma is one of the most common haematological malignancies in the USA and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). We aimed to assess the association between metformin use and progression of MGUS to multiple myeloma. METHODS We did a retrospective cohort study of patients registered in the US Veterans Health Administration database and diagnosed with MGUS between Oct 1, 1999, and Dec 31, 2009. We included patients (aged >18 years) with at least one International Classification of Diseases (9th revision) code for diabetes mellitus and one treatment for their diabetes before MGUS diagnosis. We reviewed patient-level clinical data to verify diagnoses and extract any available data for size of baseline M-protein and type of MGUS. We defined metformin users as patients with diabetes who were given metformin consistently for 4 years after their diabetes diagnosis and before multiple myeloma development, death, or censorship. Our primary outcome was time from MGUS diagnosis to multiple myeloma diagnosis. We used Kaplan-Meier curves and Cox models to analyse the association between metformin use and MGUS progression. FINDINGS We obtained data for 3287 patients, of whom 2003 (61%) were included in the final analytical cohort. Median follow-up was 69 months (IQR 49–96). 463 (23%) participants were metformin users and 1540 (77%) participants were non-users. 13 (3%) metformin users progressed to multiple myeloma compared with 74 (5%) non-users. After adjustment, metformin use was associated with a reduced risk of progression to multiple myeloma (hazard ratio 0·47, 95% CI 0·25–0·87). INTERPRETATION For patients with diabetes diagnosed with MGUS, metformin use for 4 years or longer was associated with a reduced risk of progression of MGUS to multiple myeloma. Prospective studies are needed to establish whether this association is causal and whether these results can be extrapolated to non-diabetic individuals. FUNDING Barnes-Jewish Hospital Foundation, National Institutes of Health, Agency for Healthcare Research and Quality, American Cancer Society.

Do racial disparities exist in the use of prostate cancer screening and detection tools in veterans

OBJECTIVE To determine whether racial disparities exist in the use of prostate cancer screening and detection tools in veterans. METHODS AND MATERIALS Administrative data were obtained from the Corporate Data Warehouse on a national cohort of 275,831 veterans (21% African American [AA]) between the ages of 40 and 70 years who were free of heart disease, did not have an elevated prostate specific antigen (PSA) level (>4 ng/ml), did not have other clinical signs of prostate cancer, had not been diagnosed with prostate cancer, and had not received treatment for prostate cancer between January 10, 1998 and September 30, 2000. Subjects were followed up until September 30, 2007. Regular users were defined as those with at least 1 annual visit to the Veterans Healthcare Administration (VHA) between October 1, 1998 and September 30, 2000. We sought to determine if race was significantly associated with PSA testing, the time to elevated PSA detection, the time to prostate biopsy, and the time to diagnosis of prostate cancer. Chi-square tests, logistic regression, and Cox proportional hazard models were used to test for associations between race and prostate cancer variables. RESULTS Eighty-four percent of the veterans between the ages 40 and 70 years undergo PSA testing. AA veterans are as likely as white veterans to undergo PSA testing. Screened AA veterans are more likely to have a PSA>4 ng/ml, undergo prostate biopsy, and be diagnosed with prostate cancer than screened white veterans. The time intervals between undergoing a prostate biopsy and being diagnosed with prostate cancer were statistically significantly shorter (although unlikely of clinical significance) for AA veterans with a PSA level>4 ng/ml than that for white veterans with a PSA level>4 ng/ml. When routine care in regular VHA users was compared with that of participants in major screening trials such as Prostate, Lung, Ovarian and Colon Cancer Trial and European Study of Screening for Prostate Cancer, prostate biopsy rates were lower (30% vs. 40%-86%), prostate cancer detection rates/person biopsied were higher (49% vs. 31%-45%), and incidence of prostate cancer was 1.1% vs. 4.9% to 8.3%. CONCLUSIONS Among regular users of the VHA for healthcare, no disparities toward AA veterans exist in the use of prostate cancer screening and detection tools. Any differences in prostate cancer treatment outcomes are not likely because of inequalities in the use of prostate cancer screening or detection tools.

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.

Obesity and the Transformation of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma: A Population-Based Cohort Study.

Background Multiple myeloma (MM) is one of the most common hematologic malignancies in the United States and is consistently preceded by monoclonal gammopathy of undetermined significance (MGUS). This study investigates the role of obesity in the progression of MGUS to MM. Methods A retrospective identified cohort of patients in the US Veterans Health Administration database diagnosed with MGUS between October 1, 1999, and December 31, 2009, was followed through August 6, 2013. Patient-level clinical data were reviewed to verify MM diagnosis, if any. Survival analyses utilizing interval-censored data were used to investigate the risk of progression of MGUS to MM. Statistical tests were two-sided. Results The analytic cohort consisted of 7878 MGUS patients with a median follow-up of 68 months. Within the cohort, 39.8% were overweight and 33.8% were obese; 64.1% were of white race. During follow-up, 329 MGUS patients (4.2%) progressed to MM: 72 (3.5%) normal-weight patients (median follow-up = 61.9 months), 144 (4.6%) overweight patients (median follow-up = 69.1 months), and 113 (4.3%) obese patients (median follow-up = 70.6 months). In the multivariable analysis, overweight (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.16 to 2.06) and obesity (HR = 1.98, 95% CI = 1.47 to 2.68) were associated with an increased risk of transformation of MGUS to MM. Moreover, black race was associated with a higher risk of MM (HR = 1.98, 95% CI = 1.55 to 2.54). Conclusions Obesity and black race are risk factors for transformation of MGUS to MM. Future clinical trials should examine whether weight loss is a way to prevent the progression to MM in MGUS patients.

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.

Impact of sarcopenia on treatment tolerance in United States veterans with diffuse large B-cell lymphoma treated with CHOP-based chemotherapy

While sarcopenia has been associated with decreased overall survival in diffuse large B‐cell (DLBCL) patients, the impact of sarcopenia on treatment tolerance has not been well‐studied. We evaluated the association of sarcopenia with febrile neutropenia hospitalization, treatment‐related mortality, and ability to complete standard number of cycles in a retrospective cohort of United States veterans diagnosed with DLBCL between 1998 and 2008 and treated with cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab. Baseline body composition parameters were evaluated using computed tomography analysis. In total, 522 patients were included in the study, of whom 245 (47%) had baseline sarcopenia. After controlling for other variables, baseline sarcopenia was independently associated with increased risk of febrile neutropenia hospitalization (adjusted Odds Ratio (aOR) 1.64, 95% confidence interval (CI) 1.01–2.65) and inability to complete standard number of treatment cycles (aOR 1.49, 95% CI 1.02–2.16) compared with no baseline sarcopenia. There was a non‐statistically significant trend toward higher treatment‐related mortality in sarcopenic patients than non‐sarcopenic patients (aOR 1.77, 95% CI 0.92–3.41). Sarcopenia is associated with increased risk of treatment intolerance and may be useful in guiding treatment planning and supportive care measures. Am. J. Hematol. 91:1002–1007, 2016.

Short- and Long-term weight changes among United States veterans with diffuse large B-cell lymphoma treated with CHOP chemotherapy

Identifying weight changes associated with treatment of diffuse large B-cell lymphoma (DLBCL) has the potential to improve the long-term health of survivors. A retrospective cohort of United States veterans with a new diagnosis of DLBCL between October 1, 1998 and September 30, 2008, with follow-up until April 23, 2013, was assembled. Weight changes were evaluated before, during, and after treatment in 1935 DLBCL patients who received cyclophosphamide, doxorubicin, vincristine, and prednisone, with or without rituximab (CHOP+/− R). One year prior to treatment, 79% of patients were obese or overweight. During the 12 months leading up to treatment, 57% of the cohort lost weight. Among patients surviving 24 months after treatment initiation, weight increased an average of 2.9 kg above weight at treatment completion. The weight change trends observed in these DLBCL patients suggest that weight management strategies may be an important part of long-term survivorship planning after conclusion of treatment.