Immunogenicity of adjuvanted versus high-dose inactivated influenza vaccines in older adults: a randomized clinical trial.

BACKGROUND: Adjuvanted inactivated influenza vaccine (aIIV) and high-dose inactivated influenza vaccine (HD-IIV) are U.S.-licensed for adults aged ≥ 65 years. This study compared serum hemagglutination inhibition (HAI) antibody titers for the A(H3N2) and A(H1N1)pdm09 and B strains after trivalent aIIV3 and trivalent HD-IIV3 in an older adult population. RESULTS: The immunogenicity population included 342 participants who received aIIV3 and 338 participants who received HD-IIV3. The proportion of participants that seroconverted to A(H3N2) vaccine strains after allV3 (112 participants [32.8%]) was inferior to the proportion of participants that seroconverted after HD-IIV3 (130 participants [38.5%]) at day 29 after vaccination (difference, - 5.8%; 95%CI, - 12.9% to 1.4%). There were no significant differences between the vaccine groups in percent seroconversion to A(H1N1)pdm09 or B vaccine strains, in percent seropositivity for any of the strains, or in post-vaccination GMT for the A(H1N1)pdm09 strain. The GMTs for the post-vaccination A(H3N2) and B strains were higher after HD-IIV than after aIIV3. CONCLUSIONS: Overall immune responses were similar after aIIV3 and HD-IIV3. For the primary outcome, the aIIV3 seroconversion rate for H3N2 did not meet noninferiority criteria compared with HD-IIV3, but the HD-IIV3 seroconversion rate was not statistically superior to the aIIV3 seroconversion rate. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03183908.

Safety, Reactogenicity, and Health-Related Quality of Life After Trivalent Adjuvanted vs Trivalent High-Dose Inactivated Influenza Vaccines in Older Adults: A Randomized Clinical Trial.

Importance: Trivalent adjuvanted inactivated influenza vaccine (aIIV3) and trivalent high-dose inactivated influenza vaccine (HD-IIV3) are US-licensed for adults aged 65 years and older. Data are needed on the comparative safety, reactogenicity, and health-related quality of life (HRQOL) effects of these vaccines. Objective: To compare safety, reactogenicity, and changes in HRQOL scores after aIIV3 vs HD-IIV3. Design, Setting, and Participants: This randomized blinded clinical trial was a multicenter US study conducted during the 2017 to 2018 and 2018 to 2019 influenza seasons. Among 778 community-dwelling adults aged at least 65 years and assessed for eligibility, 13 were ineligible and 8 withdrew before randomization. Statistical analysis was performed from August 2019 to August 2020. Interventions: Intramuscular administration of aIIV3 or HD-IIV3 after age-stratification (65-79 years; ≥80 years) and randomization. Main Outcomes and Measures: Proportions of participants with moderate-to-severe injection-site pain and 14 other solicited reactions during days 1 to 8, using a noninferiority test (5% noninferiority margin), and serious adverse events (SAE) and adverse events of clinical interest (AECI), including new-onset immune-mediated conditions, during days 1 to 43. Changes in HRQOL scores before and after vaccination (days 1, 3) were also compared between study groups. Results: A total of 757 adults were randomized, 378 to receive aIIV3 and 379 to receive HD-IIV3. Of these participants, there were 420 women (55%) and 589 White individuals (78%) with a median (range) age of 72 (65-97) years. The proportion reporting moderate-to-severe injection-site pain, limiting or preventing activity, after aIIV3 (12 participants [3.2%]) (primary outcome) was noninferior compared with HD-IIV3 (22 participants [5.8%]) (difference -2.7%; 95% CI, -5.8 to 0.4). Ten reactions met noninferiority criteria for aIIV3; 4 (moderate-to-severe injection-site tenderness, arthralgia, fatigue, malaise) did not. It was inconclusive whether these 4 reactions occurred in higher proportions of participants after aIIV3. No participant sought medical care for a vaccine reaction. No AECI was observed. Nine participants had at least SAE after aIIV3 (2.4%; 95% CI,1.1% to 4.5%); 3 had at least 1 SAE after HD-IIV3 (0.8%; 95% CI, 0.2% to 2.2%). No SAE was associated with vaccination. Changes in prevaccination and postvaccination HRQOL scores were not clinically meaningful and not different between the groups. Conclusions and Relevance: Overall safety and HRQOL findings were similar after aIIV3 and HD-IIV3, and consistent with prelicensure data. From a safety standpoint, this study's results support using either vaccine to prevent influenza in older adults. Trial Registration: ClinicalTrials.gov Identifier: NCT03183908.

Development of an international external quality assurance program for HIV-1 incidence using the Limiting Antigen Avidity assay.

Laboratory assays for identifying recent HIV-1 infections are widely used for estimating incidence in cross-sectional population-level surveys in global HIV-1surveillance. Adequate assay and laboratory performance are required to ensure accurate incidence estimates. The NIAID-supported External Quality Assurance Program Oversight Laboratory (EQAPOL) established a proficiency testing program for the most widely-used incidence assay, the HIV-1 Limiting Antigen Avidity EIA (LAg), with US Centers for Disease Control and Prevention (CDC)-approved kits manufactured by Sedia Biosciences Corporation and Maxim Biomedical. The objective of this program is to monitor the performance of participating laboratories. Four rounds of blinded external proficiency (EP) panels were distributed to up to twenty testing sites (7 North American, 5 African, 4 Asian, 2 South American and 2 European). These panels consisted of ten plasma samples: three blinded well-characterized HIV-1-seropositive samples that were included as replicates and an HIV-negative control. The seropositive samples spanned the dynamic range of the assay and are categorized as either recent or long-term infection. Participating sites performed the assay according to manufacturers' instructions and completed an online survey to gather information on kit manufacturer, lot of kit used, laboratory procedures and the experience of technicians. On average, fifteen sites participated in each round of testing, with an average of four sites testing with only the Maxim assay, seven testing with only the Sedia assay and five sites utilizing both assays. Overall, the Sedia and Maxim assays yielded similar infection status categorization across the laboratories; however, for most of the nine HIV+ samples tested, there were significant differences in the optical density readouts, ODn (N = 8) and OD (N = 7), between LAg kit manufacturers (p < 0.05 based on mixed effects models. The EQAPOL LAg program is important for monitoring laboratory performance as well as detecting variations between manufacturers of HIV-1incidence assays.

Morbidity, mortality and costs associated with venous thromboembolism in hospitalized patients with cancer.

BACKGROUND: Venous thromboembolism (VTE) represents a leading cause of morbidity and mortality among patients with cancer. METHODS: Hospitalization data reported on adult cancer patients at US medical centers between 1995 and 2012 were analyzed. Cancer diagnosis, presence of VTE, comorbidities, and infectious complications were based on ICD-9-CM codes. RESULTS: Nearly six million hospitalizations of 3,146,388 individual patients with cancer were reported with VTE observed in 8.4%. A single hospitalization was randomly selected for each patient with VTE diagnosed in 166,537 (5.3%) of evaluated admissions. In-hospital mortality was observed in 5.5% of patients without a VTE diagnosis and in 15.0% of those with VTE including 19.4% with a pulmonary embolism. While rates of VTE increased from 3.5% in 1995 to 6.5% in 2012, no significant reported changes in VTE imaging, length of stay (LOS) or intensive care unit (ICU) admissions were observed and mortality decreased by one-third. VTE was reported in 5.2%, 5.8% and 5.4% of patients with solid tumors, lymphoma, and leukemia, respectively. Rates of VTE were greatest among patients with pancreatic, gastric or other abdominal malignancies as well as those with ovarian, lung and esophageal cancers. The risk of VTE increased progressively from 2.3% in those with no comorbidities to over 11% in those with ≥3 major comorbidities. The strongest risk factors for VTE were infectious complications including sepsis, invasive candidiasis, pneumonia and IV line infections. Average costs per hospitalization adjusted to 2015 dollars for patients without and with VTE were $19,994 and $37,352, respectively. CONCLUSIONS: VTE among hospitalized patients with cancer has increased significantly with a major impact on hospital mortality and costs. Patients with major medical comorbidities and infectious complications are at particularly high risk.

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.

Analysis of Factors Associated With In-hospital Mortality in Lung Cancer Chemotherapy Patients With Neutropenia.

Lung cancer, compared with other solid tumors, is associated with high mortality rates from febrile neutropenia. The risk factors associated with in-hospital mortality were identified and compared for patients with lung cancer and patients with other solid tumors. Hospitalization data from the University Health Consortium database inclusive of 2004 to 2012 were analyzed. The study population included all adult patients with solid tumors who developed neutropenia. Cancer type, the presence of neutropenia, and further subgroups were determined using International Classification of Diseases, 9th revision, Clinical Modification codes. The primary study outcome was in-hospital mortality in lung cancer patients versus those with other solid tumors. Further analysis concentrated on comparisons of the 2 groups. The analysis included data from 11,111 lung cancer patients and 49,975 patients with other solid tumors. Overall, 4290 patients (7.0%) died. Lung cancer was associated with highest mortality (11.2% compared with other solid tumors, 6.1%; P < .0001). The lung cancer patients were older and more likely to have multiple comorbidities, and the risk of mortality was directly related to the number of comorbidities. Four additional risk factors for mortality were identified: pneumonia, sepsis, any infection, and intensive care unit stay. Pneumonia occurred more commonly in the lung cancer patients (26.4% vs. 10.3%) and was associated with comorbid pulmonary disease, which also occurred more often in the lung cancer patients (52.1% vs. 24.0%). We found that lung cancer patients presenting with febrile neutropenia were older, had more comorbidities, had a greater incidence of comorbid pulmonary disease, and were more likely to have pneumonia. Awareness of these risk factors for mortality should guide clinicians for more personalized approaches to chemotherapy, supportive care decisions, pneumonia and comorbidities.

A Patient Risk Model of Chemotherapy-Induced Febrile Neutropenia: Lessons Learned From the ANC Study Group.

Neutropenia and its complications, including febrile neutropenia (FN), represent major toxicities associated with cancer chemotherapy, resulting in considerable morbidity, mortality, and costs. The myeloid growth factors such as granulocyte colony-stimulating factor (G-CSF) have been shown to reduce the risk of neutropenia complications while enabling safe and effective chemotherapy dose intensity. Concerns about the high costs of these agents along with limited physician adherence to clinical practice guidelines, resulting in both overuse and underuse, has stimulated interest in models for individual patient risk assessment to guide appropriate use of G-CSF. In a model developed and validated by the ANC Study Group, half of patients were classified as high risk and half as low risk based on patient-, disease-, and treatment-related factors. This model has been further validated in an independent patient population. Physician-assessed risk of FN, as well as the decision to use prophylactic CSF, has been shown to correlate poorly with the FN risk estimated by the model. Additional modeling efforts in both adults and children receiving cancer treatment have been reported. Identification of patients at a high individual risk for FN and its consequences may offer the potential for optimal chemotherapy delivery and patient outcomes. Likewise, identification of patients at low risk for neutropenic events may reduce costs when such supportive care is not warranted. This article reviews and summarizes FN modeling studies and the opportunities for personalizing supportive care in patients receiving chemotherapy.

Risk of chemotherapy-induced neutropenic complications when treating patients with non-Hodgkin lymphoma.

INTRODUCTION: Myelosuppression induced by cancer chemotherapy is associated with considerable morbidity and mortality. Febrile neutropenia (FN) represents an oncologic emergency requiring immediate evaluation and treatment. Resulting chemotherapy dose reductions or delays may compromise disease control and survival. While non-Hodgkin lymphoma (NHL) represents a potentially curable malignancy, there are limited data on the risk of neutropenic complications. This review represents a systematic search and evidence summary of neutropenic complications reported in randomized controlled trials (RCTs) published over the past decade in adults with NHL receiving myelosuppressive chemotherapy. AREAS COVERED: Data captured include the chemotherapy regimen and dosing, the type of NHL, sample size, myeloid growth factor (MGF) use, and myelosuppression including FN and severe neutropenia and infection. EXPERT OPINION: Rates of neutropenic complications for commonly utilized chemotherapy regimens vary considerably across studies with FN reported in only one-fourth of study arms. Further challenges in interpreting reported rates are the variable and inconsistent use of MGF support and little or no information on delivered chemotherapy dose intensity. Considerable change in regimens, study populations and reporting of neutropenic events as well as the use of MGF was observed over the decade of RCTs reported. Complete and accurate reporting of treatment-related toxicities in patients receiving cancer chemotherapy is essential in both clinical trials and clinical practice.

The impact of chemotherapy dose intensity and supportive care on the risk of febrile neutropenia in patients with early stage breast cancer: a prospective cohort study.

BACKGROUND: Febrile neutropenia (FN) is a major dose-limiting toxicity of cancer chemotherapy resulting in considerable morbidity, mortality, and cost. This study evaluated the time course of neutropenic events and patterns of supportive care interventions in patients receiving chemotherapy for early-stage breast cancer treated in oncology community practices. METHODS: A prospective cohort study of adult cancer patients initiating a new chemotherapy regimen was conducted at 115 US sites. Toxicity associated with chemotherapy including neutropenic and infectious complications was recorded over four cycles. Clinical interventions were recorded including reductions in chemotherapy dose intensity and use of supportive care measures. RESULTS: A total of 1,202 patients with stage I-III breast cancer were evaluated. The majority of neutropenic (116 of 196) and infection events (179 of 325) occurred in the initial cycle. A decrease in occurrence of FN and infection was observed in the subsequent cycles, along with an increase in utilization of colony stimulating factors (CSFs), antibiotics and reductions in chemotherapy dose intensity. The overall risk of FN in all patients was 16.3%. In patients who started treatment at or near full dose intensity, the FN risk reached 21.0% without primary CSF prophylaxis and it was 9.0% with prophylaxis. There was no significant difference in FN rates by menopausal or hormone receptors status. CONCLUSIONS: The risk of neutropenic complications is greatest in the initial cycle when most patients receive full-dose chemotherapy. A decrease in neutropenic events during subsequent cycles is associated with reduced dose intensity or increased use of supportive care measures. However, the cumulative risk of FN remains high in patients with early-stage breast cancer receiving full dose chemotherapy without prophylactic measures.

Patterns of chemotherapy-associated toxicity and supportive care in US oncology practice: a nationwide prospective cohort study.

Neutropenic complications remain an important dose-limiting toxicity of cancer chemotherapy-associated with considerable morbidity, mortality, and cost. Risk of the initial neutropenic event is greatest during the first cycle. The purpose of this study was to better understand timing of neutropenic events in relation to delivered chemotherapy dose intensity and utilization of supportive care during cancer treatment. A prospective cohort study of adult patients with solid tumors or lymphoma initiating chemotherapy was conducted at 115 randomly selected US practice sites between 2002 and 2006. Chemotherapy-associated toxicities were captured in up to four treatment cycles including severe neutropenia, febrile neutropenia, and infection. Documented interventions included colony-stimulating factor (CSF), antibiotics use, and reductions in chemotherapy relative dose intensity (RDI). A total of 3638 patients with breast (39.7%), lung (23.7%), colorectal (13.6%), ovarian (8.3%) cancers, or lymphoma (14.7%) were eligible for this analysis. The majority of neutropenic and infection events occurred in the first cycle. A significant inverse relationship was observed between reductions in neutropenic and infectious events and increased utilization of measures to reduce these complications in subsequent cycles. More than 60% of patients with stage IV solid tumors underwent reductions in RDI. Patients with lymphoma and stage I-III solid tumors had less dose reductions while receiving more prophylactic CSFs. Approximately, 15% of patients received prophylactic antibiotics. While the risk of neutropenic complications remains greatest during the initial cycle of chemotherapy, subsequently instituted clinical measures in efforts to reduce the risk of these events vary with cancer type and stage.

Predictors of reduced relative dose intensity and its relationship to mortality in women receiving multi-agent chemotherapy for epithelial ovarian cancer.

OBJECTIVE: There is limited information concerning the role of relative dose intensity (RDI) on clinical outcomes in solid tumors. The objectives of our study were to evaluate the prognostic significance of RDI and predictors of reduced RDI in women with newly diagnosed advanced stage epithelial ovarian carcinoma (EOC) treated with platinum-based chemotherapy. METHODS: A multi-center retrospective study of women with FIGO stage III-IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy between 1995 and 2009 was conducted. Data were obtained to include the first four chemotherapy cycles administered. Outcomes included: (1) planned and delivered relative dose intensity (RDI), (2) progression-free (PFS) and overall (OS) survival. Survival estimates were based on Kaplan and Meier method, and multivariate analyses were based on logistic regression and Cox proportional hazards regression. RESULTS: Evaluable subjects included 325 women. With median follow-up of 34 months (range, 0.4-170), progression or recurrence was recorded in 241 (73.9%) and death in 179 (54.9%). In multivariate analysis, predictors of reduced planned RDI were: treatment off research protocols (odds ratio [OR]=4.3; P<0.001) and BSA >2m(2) (OR=6.14; P<0.001); predictors of reduced delivered RDI were: BMI over 30 kg/m(2) (OR=2.35; P=0.008) and use of carboplatin (OR=2.71; P=0.008). In multivariate analysis, the following factors were independently associated with OS: delivered RDI <85% (hazard ratio [HR]=1.71; P=0.003) and elevated CA-125 at cycle 1 (HR=2.29; P=0.017). CONCLUSION: In this retrospective analysis, reduced chemotherapy RDI for ovarian cancer was associated with lower OS, but not PFS, despite adjustment for established prognostic factors.

Risk factors for in-hospital mortality and prolonged length of stay in older patients with solid tumor malignancies.

OBJECTIVE: Hospitalized adult patients with cancer and with major comorbidities have higher mortality rates and longer duration of hospitalization. There is limited understanding of risk factors that contribute to prolonged hospitalization and mortality in older patients with solid tumors. MATERIALS AND METHODS: Risk factors associated with in-hospital mortality and prolonged length of stay (LOS) in older patients with cancer were investigated in a retrospective cohort study. Data from the University HealthSystem Consortium database included 386,377 patients age ≥ 65 years with solid tumors hospitalized between 1995 and 2003 at 133 U.S. academic medical centers. RESULTS: The overall mortality rate was 7.3%. Mortality in older patients with cancer was strongly associated with longer LOS. Almost twice as many deaths were observed among those with LOS ≥ 10 days (p<0.0001). Nearly 38% of older cancer patients who died in hospital had potentially curable disease. Primary central nervous system malignancies were most strongly associated with in-hospital mortality (OR=1.81; 1.59-2.07), followed by esophageal (OR=1.74; 1.54-1.97) and lung cancer (OR=1.57; 1.43-1.72). Male gender, African-American race, and Hispanic and Asian race/ethnicity were associated with increased risk of mortality (p<0.0001). Additional risk factors included metastatic disease, infection, neutropenia, renal, lung, hepatic, cerebrovascular disease, arterial/venous thromboembolism, heart failure, and red blood cell transfusion. Risk factors for prolonged LOS included gastric cancer, infection, venous thromboembolism and red blood cell transfusion. CONCLUSIONS: Prolonged LOS was strongly associated with mortality. Risk factors such as infection, neutropenia and red blood cell transfusion, when modified, could potentially reduce rates of prolonged LOS and mortality in older patients with cancer.

Predictors of severe and febrile neutropenia during primary chemotherapy for ovarian cancer.

OBJECTIVE: To identify factors that increase the risk of neutropenic events in women with advanced ovarian carcinoma receiving initial chemotherapy. METHODS: Multi-center retrospective study of women with FIGO stage III-IV epithelial ovarian cancer treated postoperatively with multi-agent intravenous chemotherapy from 1995 to 2008. Outcomes were severe (SN; absolute neutrophil count [ANC]<500/mm(3)) and febrile neutropenia (FN; ANC<1000/mm(3) and temperature>38.1°C). Cumulative risk of neutropenic events was estimated by Kaplan Meier method. Multivariate analysis was by Cox proportional hazard regression. RESULTS: Three hundred twenty-six patients met inclusion criteria. There were 251 SN events among 140 (43%) patients and 24 FN events among 22 (7%) patients. Univariate predictors of SN were body surface area<2.0m(2) (p=0.03), body mass index (BMI)<30 kg/m(2) (p<0.01), Caucasian race (p<0.01), treatment on research protocols (p<0.01), non-carboplatin-containing regimens (p<0.01), and planned relative dose intensity (RDI)>85% of standard (p=0.02). Women over age 60 were more likely to develop FN (p=0.05). Multivariate predictors of SN were treatment on research protocols (hazard ratio [HR] 1.93; p<0.01), Caucasian race (HR 2.13; p=0.01), and planned RDI>85% (HR 1.69; p=0.05); predictors of FN were age>60 (HR 2.84; p=0.05) and non-carboplatin containing regimens (HR 4.06; p<0.01). CONCLUSION: While SN is fairly common, FN occurs infrequently in women with EOC undergoing taxane and platin-based chemotherapy and primary prophylactic growth factor support is not indicated. However, women older than 60 years of age receiving non-carboplatin containing regimens are at higher risk for FN and warrant closer surveillance.

Predicting individual risk of neutropenic complications in patients receiving cancer chemotherapy.

BACKGROUND: A prospective cohort study was undertaken to develop and validate a risk model for neutropenic complications in cancer patients receiving chemotherapy. METHODS: The study population consisted of 3760 patients with common solid tumors or malignant lymphoma who were beginning a new chemotherapy regimen at 115 practice sites throughout the United States. A regression model for neutropenic complications was developed and then validated by using a random split-sample selection process. RESULTS: No significant differences in the derivation and validation populations were observed. The risk of neutropenic complications was greatest in cycle 1 with no significant difference in predicted risk between the 2 cohorts in univariate analysis. After adjustment for cancer type and age, major independent risk factors in multivariate analysis included: prior chemotherapy, abnormal hepatic and renal function, low white blood count, chemotherapy and planned delivery ≥85%. At a predicted risk cutpoint of 10%, model test performance included: sensitivity 90%, specificity 59%, and predictive value positive and negative of 34% and 96%, respectively. Further analysis confirmed model discrimination for risk of febrile neutropenia over multiple chemotherapy cycles. CONCLUSIONS: A risk model for neutropenic complications was developed and validated in a large prospective cohort of patients who were beginning cancer chemotherapy that may guide the effective and cost-effective use of available supportive care.

Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: a systematic review.

PURPOSE: To evaluate the risk of acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) and overall mortality in patients receiving chemotherapy with or without granulocyte colony-stimulating factor (G-CSF), a systematic review of randomized controlled trials (RCTs) was conducted. METHODS: Electronic databases searched through October 2008 identified 3,794 articles for initial screening. Eligibility included solid tumor or lymphoma patients randomly assigned to chemotherapy with or without G-CSF support, > or = 2 years of follow-up, and reporting AML/MDS or all second malignancies. Dual blinded data extraction was performed. Relative risk (RR) and absolute risk (AR) estimates +/- 95% CIs were calculated by the Mantel-Haenszel method. RESULTS: In the 25 eligible RCTs, 6,058 and 6,746 patients were randomly assigned to receive chemotherapy with and without initial G-CSF support, respectively. At mean and median follow-up across studies of 60 and 53 months, respectively, AML/MDS was reported in 22 control patients and 43 G-CSF-treated patients, with an estimated RR of 1.92 (95% CI, 1.19 to 3.07; P = .007) and AR increase of 0.41% (95% CI, 0.10% to 0.72%; P = .009). Deaths were reported in 1,845 patients randomly assigned to G-CSF and in 2,099 controls, for estimates of RR and AR decrease of 0.897 (95% CI, 0.857 to 0.938; P < .001) and 3.40% (95% CI, 2.01% to 4.80%; P < .001), respectively. Greater RR reduction for mortality was seen for both larger studies (P = .05) and greater chemotherapy dose-intensity (P = .012). CONCLUSION: Delivered chemotherapy dose-intensity and risk of AML/MDS are increased but all-cause mortality is decreased in patients receiving chemotherapy with G-CSF support. Greater reductions in mortality were observed with greater chemotherapy dose-intensity.

Dose intensity and hematologic toxicity in older breast cancer patients receiving systemic chemotherapy.

BACKGROUND: This prospective study evaluated patient and treatment characteristics that contributed to hematologic toxicity in older breast cancer patients treated with curative intent in the community setting. METHODS: Data were collected on 1224 patients with stage I through III breast cancer, of whom 207 were aged > or =65 years (grading determined according to the American Joint Committee on Cancer staging system). Primary outcome measures included anemia, thrombocytopenia, severe neutropenia, febrile neutropenia, and both planned and actual relative dose intensity (RDI). Comparisons between older and younger patients regarding hematologic toxicity and reductions in RDI were based on univariate and multivariate logistic regression analyses. RESULTS: The neutropenic complication rate in older patients (45.1%) was not significantly different from that in the younger patients (43.7%). There were also no significant differences in rates of anemia or thrombocytopenia. Approximately 34.0% of the older patients received RDI <85% compared with 20.0% among younger patients (P < .01). Fewer older patients received anthracycline-based chemotherapy (64.3% compared with 83.8% in younger patients, P < .01). Fewer older patients received prophylactic white blood cell colony-stimulating factor (18.4%) compared with younger patients (28.0%) (P < .01). CONCLUSIONS: There were no significant differences noted with regard to chemotherapy-related hematologic toxicities between older and younger breast cancer patients in this large prospective observational study. This may be explained, in part, by more frequent reductions in RDI and less frequent utilization of anthracyclines among older patients.

Variation in the cost of medications for the treatment of colorectal cancer.

OBJECTIVE: To evaluate the economic burden of colorectal cancer (CRC) treatment on the healthcare system as treatment costs have risen 340-fold during the past 5 years. STUDY DESIGN: Nationwide registry. METHODS: Patients with CRC (N = 421) were selected from an observational prospective patient registry of US oncology clinics. The 8 most commonly prescribed regimens were identified. Standard dosing schedules were set for these regimens based on a literature review and expert CRC oncologist input. Each chemotherapeutic regimen was broken down into its component agents, and regimen costs were calculated by summing the costs of each agent per regimen. Price-per-milligram costs were calculated from Health Care Financing Administration Common Procedural Coding System codes for specific drugs. Patient population, temporal, and regional trends were studied among standard regimens. RESULTS: The most common regimens were 5-fluorouracil-leucovorin calcium (5-FU/LV) (147 patients [34.9%]), fluorouracil-leucovorin-irinotecan hydrochloride (FOLFIRI) (111 patients [26.4%]), and fluorouracil-leucovorin-oxaliplatin (103 patients [24.5%]). The remaining 60 patients (14.3%) received irinotecan, capecitabine, and oxaliplatin; oxaliplatin; irinotecan in combination with oxaliplatin; or a miscellaneous regimen. The largest cost differential for 6 cycles of planned treatment was $35,971 between FOLFIRI ($36,999) and 5-FU/LV ($1028). On a per-week basis, treatment costs may differ by more than 91 times. Patient utilization of growth factors, ancillary medications, and monoclonal antibodies added significant costs. CONCLUSIONS: The costs of CRC regimens varied considerably. Trends in treatment regimens have changed notably over time, with newer agents and supportive drugs adding substantially to treatment costs.

Risk and timing of neutropenic events in adult cancer patients receiving chemotherapy: the results of a prospective nationwide study of oncology practice.

This study was undertaken to describe the relationship between the occurrence and timing of neutropenic events and chemotherapy treatment in a community-based population of patients with cancer. The study included 2962 patients with breast, lung, colorectal, lymphoma, and ovarian cancers from a prospective U.S. registry of patients initiating a new chemotherapy regimen. Detailed patient-, disease-, and treatment-related data, including toxicities, were captured at baseline, the beginning of each cycle, and each midcycle blood draw for up to 4 cycles of treatment. Primary outcomes included febrile neutropenia (FN), severe neutropenia without fever/ infection, and relative dose intensity (RDI). Thirty-seven percent of patients were aged 65 years or older, 43.5% had an Eastern Cooperative Oncology Group performance status of 1 or greater, and 27% had 1 or more comorbidities. Reductions in RDI to less than 85% of standard in the first cycle were planned in 23.6% of patients, whereas primary colony-stimulating factor prophylaxis was used in 18.2%. In the first 3 cycles of treatment, 10.7% of patients experienced FN, with most of these events (58.9%) occurring in the first cycle. This first-cycle pattern was consistently observed despite wide variations in event rates by tumor type, disease stage, chemotherapy regimen and dose, and patient characteristics. Despite frequent planned reductions from standard RDI, the incidence of FN remains high in community oncology practice in the United States. Improved methods of pretreatment assessment of patient risk factors for neutropenia are needed.

Dose intensity and hematologic toxicity in older cancer patients receiving systemic chemotherapy.

BACKGROUND: This prospective study was undertaken to evaluate patient and treatment characteristics that contribute to hematologic toxicity in older cancer patients. METHODS: A nationwide study of 115 community oncology practices was conducted between 2002 and 2005 with data collected on 976 patients who had received chemotherapy for common malignancies, including lung cancer, colorectal cancer, breast cancer, ovarian cancer, genitourinary cancer, and lymphoma. Primary outcomes included severe neutropenia (SN) and febrile neutropenia (FN). Secondary outcomes included delivered relative dose intensity (RDI) <85%, dose delays > or =15% days, and reductions > or =15%. RESULTS: Approximately 50% of both patients with early-stage disease and patients with advanced-stage disease received an actual RDI <85%, and this rate reached 60% in the oldest group (aged >80 years). Increasing age was associated with lower actual RDI (P = .030) and averaged 87.5% across all elderly age groups. A decreasing trend in SN or FN events occurred with increasing age (P for trend = .039), with the majority of initial neutropenic events occurring in Cycle 1 for all age groups. Among the patients who received an actual RDI > OR =85%, there was no significant difference in SN or FN by age group or disease stage. Independent risk factors for the development of SN or FN included cancer type, planned RDI > or =85%, body surface area < or =2m(2), anthracycline- or platinum-based regimens, previous chemotherapy, elevated blood urea nitrogen, and alkaline phosphatase. Neutropenic complications decreased significantly with primary colony-stimulating factor (CSF) prophylaxis (coefficient of determination [R(2)] = 0.260; c-statistic = 0.782). CONCLUSIONS: Among cancer patients aged > or =70 years, 50% of whom received relatively full-dose chemotherapy, increasing age alone did not increase the risk of hematologic toxicity.

Social and racial differences in selection of breast cancer adjuvant chemotherapy regimens.

PURPOSE: Breast cancer outcomes are worse among black women and women of lower socioeconomic status. The purpose of this study was to investigate racial and social differences in selection of breast cancer adjuvant chemotherapy regimens. METHODS: Detailed information on patient, disease, and treatment factors was collected prospectively on 957 patients who were receiving breast cancer adjuvant chemotherapy in 101 oncology practices throughout the United States. Adjuvant chemotherapy regimens included in any of several published guidelines were considered standard. Receipt of nonstandard regimens was examined according to clinical and nonclinical factors. Differences between groups were assessed using chi2 tests. Multivariate logistic regression was used to identify factors associated with use of nonstandard regimens. RESULTS: Black race (P = .008), lower educational attainment (P = .003), age 70 years (P = .001), higher stage (P < .0001), insurance type (P = .048), employment status (P = .045), employment type (P = .025), and geographic location (P = .021) were associated with the use of nonstandard regimens in univariate analyses. In multivariate analysis, black race (P = .020), lower educational attainment (P = .024), age > or = 70 years (P = .032), and higher stage (P < .0001) were associated with receipt of nonstandard regimens. CONCLUSION: The more frequent use of non-guideline-concordant adjuvant chemotherapy regimens in black women and women with lower educational attainment may contribute to less favorable outcomes in these populations. Addressing such differences in care may improve cancer outcomes in vulnerable populations.