Search

In the clinical setting,the frequency of adverse effects is directly linked to treatment results but during chemotherapy,they are unavoidable.One of them is stomatitis,a distressing toxic effect.In patients receiving myelosuppressive chemotherapy for solid tumors,the prevalence of stomatitis is 5-40% while its prevalence in patients receiving stem cell transplantation is 75-100%.Stomatitis-associated pain is the main source of cancer treatment-related pain and in some patients it is so severe that narcotic analgesia is required.Oxidative stress may also be associated with chemotherapy-induced stomatitis and a mouthwash containing allopurinol,rebamipide and camostat for the removal of free radicals is widely used for the prevention and treatment of such stomatitis.However,such agents are not covered by the Japanese National Health Insurance scheme and there is little scientific evidence for their antioxidative properties and effectiveness in the prevention and treatment of chemotherapy-induced stomatitis.We therefore attempted to establish a more useful mouthwash.In the first part of this study,we investigated the antioxidant properties of various compounds.We then used H2O2-induced HO-1-N-1 cell injury as a model of stomatitis and found that epigallocatechin gallate had a strong preventive effect against it.Epigallocatechin gallate would therefore be a good component of a mouthwash for the prevention of stomatitis in patients undergoing cancer chemotherapy.

Chemotherapy-induced anemia (CIA) commonly occurs in cancer patients receiving conventional myelosuppressive chemotherapy. Two national guidelines regarding the use of erythropoiesis-stimulating agents (ESAs) in CIA were released in 2002. Because of poorer disease outcomes and increased risk of adverse events associated with ESAs in recent studies, the use of ESAs has been increasingly restricted in practice guidelines in the years 2007 and 2008.The aim of this study was to provide a baseline for adherence to national guidelines in the use of ESAs for CIA between 2002 and 2006.This retrospective study used the Varian Medical Oncology database (Varian Medical Systems, Inc., Palo Alto, California) of electronic medical records, representing 17 outpatient oncology organizations at 71 clinic locations in the United States. Adults diagnosed with any malignant neoplasm who started conventional cytotoxic chemotherapy between January 1, 2002, and September 30, 2006, were included. The proportion of patients receiving an ESA was calculated by hemoglobin (Hb) level during each chemotherapy cycle, stratified by line of chemotherapy and year. Logistic regression modeling identified predictors of ESA use in anemic patients during the first chemotherapy cycle.The records of 17,731 cancer patients were evaluated. Median (SD) age was 61 (13) years, and 58.9% were female. Most patients (84.1%) had a solid tumor. Many patients (41.3%) received platinum containing chemotherapy and 74.4% received combination chemotherapy. During the first 5 cycles of first-line chemotherapy among patients with CIA (Hb11 g/dL), ESAs were used by 55.8% of patients at cycle 1 and 68.9% at cycle 5. ESA use in CIA patients increased across lines of chemotherapy and time. Few patients (2.8%) received an ESA at Hb13 g/dL. The statistically significant predictors of ESA use included age65 years, eastern US residence, private health insurance, community-based care, and solid tumors, especially lung cancer.The patterns we observed were generally consistent with prevailing ESA labels and national guidelines during 2002 through 2006. Although ESA use in patients with CIA increased over chemotherapy cycles, lines of chemotherapy, and time,70% of CIA episodes were treated with ESAs during the initial 5 chemotherapy cycles.

Submitted by Guilherme Lemeszenski (guilherme@nead.unesp.br) on 2013-08-22T19:00:05Z No. of bitstreams: 1 S0103-84782009000200045.pdf: 272340 bytes, checksum: dd053f15ff76a098d56490cf0dd20ec8 (MD5) Made available in DSpace on 2013-08-22T19:00:05Z (GMT). No. of bitstreams: 1 S0103-84782009000200045.pdf: 272340 bytes, checksum: dd053f15ff76a098d56490cf0dd20ec8 (MD5) Previous issue date: 2009-04-01 Made available in DSpace on 2013-09-30T19:57:57Z (GMT). No. of bitstreams: 2 S0103-84782009000200045.pdf: 272340 bytes, checksum: dd053f15ff76a098d56490cf0dd20ec8 (MD5) S0103-84782009000200045.pdf.txt: 21903 bytes, checksum: 1415f895f5eb6fefa51a0eec5b501108 (MD5) Previous issue date: 2009-04-01 Submitted by Vitor Silverio Rodrigues (vitorsrodrigues@reitoria.unesp.br) on 2014-05-20T13:14:04Z No. of bitstreams: 2 S0103-84782009000200045.pdf: 272340 bytes, checksum: dd053f15ff76a098d56490cf0dd20ec8 (MD5) S0103-84782009000200045.pdf.txt: 21903 bytes, checksum: 1415f895f5eb6fefa51a0eec5b501108 (MD5) Made available in DSpace on 2014-05-20T13:14:04Z (GMT). No. of bitstreams: 2 S0103-84782009000200045.pdf: 272340 bytes, checksum: dd053f15ff76a098d56490cf0dd20ec8 (MD5) S0103-84782009000200045.pdf.txt: 21903 bytes, checksum: 1415f895f5eb6fefa51a0eec5b501108 (MD5) Previous issue date: 2009-04-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Este estudo teve como objetivo descrever o primeiro relato de transplante de medula óssea (TMO) em cães no Brasil. Para tanto, um rottweiller com linfoma cutâneo foi submetido ao protocolo quimioterápico de Madison-Wisconsin pelo período de 12 semanas, seguido pelo transplante autólogo de medula óssea. Para tanto, 10mL kg-1 de medula óssea foram coletados de ambas as cristas ilíacas do paciente, simultaneamente; sendo o volume final criopreservado em freezer a -80°C. A etapa de condicionamento foi realizada com a administração da ciclofosfamida, por via intravenosa, na dose de 400mg m-2. A reinfusão da medula óssea foi realizada após o descongelamento da bolsa em banho-maria a 37°C. As contagens de células nucleadas de alíquotas obtidas da bolsa de medula óssea antes do congelamento e após o descongelamento demonstram pequena perda relativa de células nucleadas (35,10 e 31,80 x10³µL-1, respectivamente). A neutropenia decorrente da ciclofosfamida foi revertida com a administração de um fator estimulador de colônia de granulócitos (G-CSF), que foi capaz de acelerar a reconstituição hematopoética. O paciente encontra-se no dia + 360 pós-transplante em remissão completa da doença. Este trabalho indicou que o TMO autólogo em um cão com linfoma, submetido à quimioterapia mielossupressora, foi potencialmente seguro e efetivo. The objective of this study is to provide the first report of bone marrow transplantation (BMT) in dogs in Brazil. A Rottweiler with cutaneous lymphoma was submitted to a twelve-week Madison-Wisconsin chemotherapy protocol followed by autologous bone marrow transplantation. For this, 10mL kg-1 of bone marrow was collected simultaneously from both iliac crests and cryopreserved in a freezer at -80°C. The conditioning step was performed by administering cyclophosphamide by intravenous route at 400mg m-2. Bone marrow was reinfused after defrosting in a water bath at 37°C. Bone marrow nucleated cell counts before and after freezing, showed a small relative loss of nucleated cells (35.10 and 31.80x10³µL-1 , respectively). Cyclophosphamide induced neutropenia which was reverted by a granulocyte colony-stimulating factor (G-CSF) capable of stimulating hematopoetic reconstitution. on the day 360 after transplant the patient was found to be in complete remission. This study indicates that autologous BMT in a dog with lymphoma submitted to myelosuppressive chemotherapy was potentially safe and effective. Universidade Estadual Paulista Faculdade de Ciências Agrárias e Veterinárias Departamento Clínica e Cirugia Veterinária Centro Universitário Barão de Mauá Universidade Estadual Paulista Faculdade de Ciências Agrárias e Veterinárias Universidade Estadual Paulista Faculdade de Ciências Agrárias e Veterinárias Departamento Clínica e Cirugia Veterinária Universidade Estadual Paulista Faculdade de Ciências Agrárias e Veterinárias FAPESP: 05/01617-8 FAPESP: 06/03300-1

Purpose This article highlights the clinical impact of chemotherapy-induced neutropenia (CIN) and reviews the clinical evidence supporting the updated guideline recommendations from leading scientific organizations that focus on cancer care regarding the use of myeloid growth factors to reduce the incidence of febrile neutropenia (FN) from chemotherapy. The aim is to provide insight for practicing pharmacists regarding how they can be more proactive in developing best-practice strategies for the management of CIN as well as the prevention of FN. Summary CIN, the primary dose-limiting toxicity of chemotherapy, is common in many tumor types that are treated with myelosuppressive chemotherapy and occurs with the greatest frequency in the first cycle of treatment. Treatment with myeloid growth factors, or colony-stimulating factors (CSFs), has shown to be effective in reducing the risk, severity, and duration of FN from chemotherapy. Despite recent revisions to various clinical guidelines that have resulted in alignment on the recommendation for prophylactic CSF use in patients with a greater than or equal to 20% risk of developing FN, a gap remains between actual clinical usage and best practice. Pharmacists are key members of multidisciplinary health care teams and are uniquely positioned to evaluate current practice and develop strategies that ensure appropriate CSF use. This paper summarizes the recent changes to CSF guidelines, reviews clinical data that support those changes, and discusses strategies for pharmacist involvement in the management of CIN and FN prevention using real-world examples of improvement initiatives. Conclusion Neutropenia is a dose-limiting toxicity of chemotherapy that has significant implications for effective cancer treatment and patient health outcomes. Pharmacists are uniquely positioned to perform various interventions, which help ensure appropriate CSF use and improve the management of CIN.

Significant changes in the epidemiology of infectious complications in cancer patients have emerged during the past decade. Among blood culture isolates from febrile neutropenic patients, Gram-positive pathogens have become predominant, and an increasing spread of methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci must be taken into consideration. Risk factors such as indwelling venous catheters or chemotherapy-induced mucosal damage are associated with an increased incidence of Gram-positive infections. Invasive fungal infections, particularly invasive aspergillosis, have become most important in severely neutropenic patients and are associated with fatality rates of 40-60%. The use of nucleoside analogues and the CD52-antibody alemtuzumab induce a long-lasting lymphopenia facilitating the occurrence of opportunistic infections specifically caused by viruses and fungi. In elderly patients undergoing intensive myelosuppressive chemotherapy, infectious complications may be managed as successfully as in younger patients by appropriate antimicrobial therapy. The broad use of fluoroquinolones for antibacterial prophylaxis in neutropenic patients may lead to very high resistance rates among Gram-negative bacilli such as E. coli. In patients given moxifloxacin for infection prevention, unacceptably large numbers of Clostridium difficile-associated enterocolitis have been reported.

Background Cost of neutropenic complications of myelosuppressive chemotherapy has been reported to be substantial. Prior research, however, has focused on initial hospitalization only and has failed to account for follow-on care. Patients and methods Using a US health-care claims database, all adult cancer patients who received a course of chemotherapy were identified. For each such patient, each unique cycle of chemotherapy within the course and each occurrence of neutropenic complications within these cycles were characterized. Patients developing neutropenic complications in a given cycle (neutropenia patients), starting with the first, were matched (1 : 1) to those who did not develop neutropenic complications in that cycle (comparison patients), and health-care costs (i.e. expenditures) were tallied for each matched pair. Results Neutropenia patients (n = 373) and comparison patients were similar in terms of baseline characteristics. Costs of neutropenia-related care were $12 397 (95% confidence interval $10 274–$14 754) higher for neutropenia versus comparison patients [$14 407 ($12 357–$16 743) versus $2010 ($1490–$2553)]. Among neutropenia patients, mean cost of initial hospitalization for neutropenic complications was $7813 ($6537–$9379); cost of all subsequent neutropenia-related care averaged $6594 ($5217–$8272). Conclusions Neutropenic complications of myelosuppressive chemotherapy are costly. Prior research focusing on initial hospitalization only may have underestimated the cost of these complications by as much as 40%.

Purpose The SIGNIFICANT (Simple Investigation in Neutropenic Individuals of the Frequency of Infection after Chemotherapy ± Antibiotic in a Number of Tumours) trial reported a reduction in febrile episodes (FEs) among 1,565 patients with solid cancers and lymphomas receiving cyclical, myelosuppressive chemotherapy (causing grade 4 neutropenia) in a randomized, placebo-controlled, double-blind trial of levofloxacin (P = .01). In response to concerns that increased antibacterial prescribing selects for microbial resistance, we examined our data to explore the rationale for more limited prophylaxis. Patients and Methods The risk of FE was calculated for control patients on first versus nonfirst cycles, with or without first-cycle FE, and within subgroups defined by cancer type, performance status (PS), age, and treatment context (adjuvant v nonadjuvant). Using the randomized trial data, the prophylactic efficacy of levofloxacin was examined for the same subgroups. Results The per-cycle FE incidence was much lower on nonfirst (3.3%) versus first cycles (8.0%). Prophylaxis was less effective for nonfirst (odds ratio [OR] = 0.78; P = .16) compared with first cycles (OR = 0.42; P < .001). However, FE on cycle 1 predicted a much higher risk of FE and a trend to continued prophylactic efficacy on subsequent cycles. FE rate was greatest for testicular cancer (27.9%), then small-cell lung cancer (17.3%), and lowest for breast cancer (11.5%). Prophylactic efficacy was consistent across age, sex, PS, treatment context, and disease type (except possibly non-Hodgkin's lymphoma). Conclusion Under pressure to limit antibacterial use, these exploratory data support offering prophylactic levofloxacin on cycle 1 only of myelosuppressive cancer chemotherapy and on subsequent cycles after a cycle-1 fever. Prophylactic levofloxacin is effective regardless of age, PS, or tumor type.

Hematopoietic growth factors alone or in combination with myelosuppressive chemotherapy are used to mobilize peripheral blood stem cells for autologous transplantation. To identify characteristics of successful mobilization with granulocyte colony-stimulating factor (G-CSF) alone and to study the impact of immediate chemotherapy mobilization following G-CSF mobilization, we treated 175 chemotherapy sensitive lymphoma patients with G-CSF (G) mobilization and leukapheresis followed by chemotherapy plus G-CSF (CG) mobilization and leukapheresis and then autologous transplantation. Patients with stage I/II disease at diagnosis andor =5 years from diagnosis were more likely to mobilize successfully with G-CSF alone (G). CG mobilization led to superior stem cell yields compared to the preceding mobilization with G (median 2.37 vs 1.37 ( x 10(6)CD34+ cells/kg); P0.0001). Patients (n=58, 33%) with successful G-CSF mobilization (or =2 x 10(6) CD34+ cells/kg) had quicker platelet recovery and improved progression free and overall survival compared to patients who had adequate collection only after chemotherapy mobilization or to those who failed to collect an adequate graft with either type of mobilization. The poor clinical outcome of patients with difficult mobilization using either method identifies them as a high-risk group who might benefit from alternative therapies.

The myelotoxicity of most chemotherapeutic regimens used to treat children and adolescents with cancer require the use of daily subcutaneous administration of hematological growth factors (mainly granulocyte colony-stimulating factor). Recently, pegfilgrastim (Neulasta), a product with a long half-life, resulting in once-per-cycle dosage, was introduced to prevent neutropenia in adults, and provided safety and efficacy similar to that provided by daily injection of filgrastim. To evaluate retrospectively the use of pegfilgrastim in children with cancer, we conducted a single-center retrospective study evaluating the use of pegfilgrastim in patients over 40 kg, who received chemotherapy for cancer from September 2003 to December 2005. A single subcutaneous injection of pegfilgrastim 100 microg/kg (maximum dose 6 mg) per chemotherapy cycle in children receiving myelosuppressive chemotherapy was given. One hundred and twenty-six administrations of pegfilgrastim were analyzed in 28 pediatric patients treated for cancer (11 girls, 17 boys) with a median age of 14.5 years (range 12-18 years) and median weight of 50.5 kg (range 40-82 kg). Patients received a median dose of pegfilgrastim of 100 microg/kg (range 73-117). The median total number of injections per patient was 4 (range 1-14). The incidence of grade 4 neutropenia by cycle was 48%, the mean duration of neutropenia was 3 days (range 1-13 days). The median values of absolute neutrophil count nadir was 0.425 x 10(9)/l (range 0-9.9 x 10(9)). Febrile neutropenia occurred in 18 of the 126 patients on pegfilgrastim use (14%) with full recovery in all patients. The median total duration of intravenous antibiotic therapy was 5 days (range 2-14 days). Bone pain (four) and headaches (two) were the most frequent adverse events reported. No correlation was found between the administered dose of Neulasta and hematological data. In conclusion, the use of pegfilgrastim was safe and well tolerated in children with cancer treated with myelosuppressive chemotherapy. Safety and efficacy of pegfilgrastim must be compared with filgrastim and evaluated in younger children with lower body weight.

Lipegfilgrastim, a glycoPEGylated recombinant granulocyte colony-stimulating factor (G-CSF), reduces neutropenia duration and febrile neutropenia (FN) incidence in patients with cancer receiving myelosuppressive chemotherapy. A phase 3 trial of lipegfilgrastim was conducted in patients with advanced non-small cell lung cancer (NSCLC) receiving cisplatin/etoposide (which produces mild-to-moderate myelosuppression). Because patients aged65 years are at higher risk for FN versus younger patients, this post hoc analysis compared outcomes in elderly (65 years) versus younger participants in this trial.Patients were randomized 2:1 to receive a once-per-cycle single subcutaneous injection of lipegfilgrastim 6 mg or placebo, with up to 4 cycles of every-3-week cisplatin (day 1) and etoposide (days 1-3). The primary end point was FN incidence during cycle 1. Outcomes were compared across treatment groups and by age groups (≤65 and65 years).For patients aged ≤65 years, FN incidence during cycle 1 was similar in the lipegfilgrastim and placebo groups (3.0 vs 3.2 %, respectively), whereas for elderly patients, there was a reduction in FN incidence with lipegfilgrastim (0 vs 13.3 %, respectively). In both age subgroups, lipegfilgrastim showed a propensity to reduce the incidence and duration of severe neutropenia, time to absolute neutrophil count (ANC) recovery, and depth of ANC nadir. Adverse events were generally similar between groups.This analysis suggests that in patients with a higher FN risk, such as the elderly patients of this study, lipegfilgrastim reduces not only the duration of severe neutropenia but also the incidence of FN.

BACKGROUND A wide variety of myelosuppressive chemotherapy regimens are used for the treatment of cancer in clinical practice. Neutropenic complications, such as febrile neutropenia, are among the most common side effects of chemotherapy, and they often necessitate delays or reductions in doses of myelosuppressive agents. Reduced relative dose intensity (RDI) may lead to poorer disease-free and overall survival. METHODS Using the McKesson Specialty Health/US Oncology iKnowMed electronic health record database, we retrospectively identified the first course of adjuvant or neoadjuvant chemotherapy received by patients without metastases who initiated treatment between January 1, 2007, and March 31, 2011. For each regimen, we estimated the incidences of dose delays (≥7 days in any cycle of the course), dose reductions (≥ 15% in any cycle of the course), and reduced RDI (

Chemotherapy-induced neutropenia (CIN) is the major dose-limiting toxicity of systemic chemotherapy and it is associated with significant morbidity, mortality and treatment cost. The aim of the present study was to identify the risk factors that may predispose pediatric cancer patients who receive myelosuppressive chemotherapy to CIN and associated sequelae. A total of 113 neutropenia episodes were analyzed and the risk factors for CIN were classified as patient-specific, disease-specific and regimen-specific, while the consequences of CIN were divided into infectious and dose-modifying sequelae. The risks and consequences were analyzed to target high-risk patients with appropriate preventive strategies. Among our patients, 28% presented with a single neutropenia attack, while 72% experienced recurrent attacks during their treatment cycles. The mean absolute neutrophil count was 225.5±128.5 ×109/l (range, 10-497 ×109/l), starting 14.2±16.3 days (range, 2-100 days) after the onset of chemotherapy and resolving within 11.2±7.3 days, either with (45.1%) or without (54.9%) granulocyte colony-stimulating factor (G-CSF). No significant association was observed between any patient characteristics or disease stage and the risk for CIN. However, certain malignancies, such as acute lymphocytic leukemia (ALL), neuroblastoma and Burkitt's lymphoma, and certain regimens, such as induction block for ALL and acute myelocytic leukemia, exerted the most potent myelotoxic effect, with severe and prolonged episodes of neutropenia. G-CSF significantly shortened the duration of the episodes and enhanced bone marrow recovery. Febrile neutropenia was the leading complication among our cases (73.5%) and was associated with several documented infections, particularly mucositis (54.9%), respiratory (45.1%), gastrointestinal tract (38.9%) and skin (23.9%) infections. A total of 6% of our patients succumbed to infection-related complications. Neutropenia was responsible for treatment discontinuation (13.3%), dose delay (13.3%) and dose reduction (5.3%) in our patients. The mean cost for each episode in our institution was 9,386.5±6,688.9 Egyptian pounds, which represented a significant burden on health care providers.

Purpose The aim of this study was to demonstrate lipegfilgrastim superiority versus placebo in adults with non-small cell lung cancer receiving myelosuppressive chemotherapy. Methods This phase III, double-blind study randomized chemotherapy-naive patients to receive cisplatin and etoposide with either lipegfilgrastim 6 mg or placebo. Because of the placebo control, patients at individual high risk for febrile neutropenia (FN; ≥20%) were excluded. Study drug was administered on day 4 (24 h after chemotherapy) of a 21-day cycle for ≤4 cycles. Primary efficacy measure was FN incidence in cycle 1. Secondary assessments included duration of severe neutropenia (DSN), absolute neutrophil count (ANC) profile, and adverse events (AEs). Results The study included 375 patients (lipegfilgrastim, n = 250; placebo, n = 125). Lipegfilgrastim superiority for FN incidence in cycle 1 was not achieved but incidence was lower (2.4%) versus placebo (5.6%). Cycle 1 mean DSN was significantly shorter for lipegfilgrastim (0.6 ± 1.1 days) versus placebo (2.3 ± 0.5 days; p

A phase 1 pharmacokinetic (PK) and pharmacodynamic (PD) study was conducted to demonstrate similarity of a proposed pegfilgrastim biosimilar to its reference product. In a single‐dose, randomized, assessor‐blinded, 2‐way crossover, active‐controlled PK/PD study, 66 healthy adults received the proposed pegfilgrastim biosimilar and US‐licensed pegfilgrastim reference product. Primary end points were pegfilgrastim AUCt and Cmax (PK), and absolute neutrophil count AUECt and Emax (PD). Safety and immunogenicity were also measured. Fifty‐six subjects completed both arms of the study. Mean pegfilgrastim concentration–time profile for both products was similar, with the 90% confidence intervals (CI) of the relative mean ratio for the primary end points falling within the predefined acceptance criteria of 80%–125% (91.7%–116.1% and 86.7%–110.2% for AUCt and Cmax, respectively). PD similarity was also demonstrated by the 95%CI of the relative mean ratio of the primary end point parameters within the predefined acceptance margins of 80%–125% (96.0%–101.6% and 92.6%–100.1% for AUECt and Emax, respectively). No statistically meaningful PK/PD differences were observed. No clinically meaningful safety or immunological differences were observed with the proposed pegfilgrastim biosimilar that were not previously identified with the reference product. The proposed pegfilgrastim biosimilar product is highly similar to the reference product with regard to PK/PD.

Background There is recent evidence supporting the safety and efficacy of same-day dosing of pegfilgrastim in patients undergoing chemotherapy. Objective To determine the cost-effectiveness of pegfilgrastim on day 1 (D1) versus day 2 (D2) for primary prevention of neutropenia in women receiving chemotherapy. Materials and Methods A cost-utility model was designed comparing standard D2 versus D1 administration of pegfilgrastim to ovarian cancer patients receiving chemotherapy with an intermediate risk (10–15%) of febrile neutropenia (FN). Rates of FN despite prophylaxis were modeled as 10% for D1 and 5% for D2. Societal costs associated with D2 injection ($175.71) were incorporated. Quality of life (QOL) was modeled from published data; we assumed a small decrement in QOL on treatment days. Sensitivity analyses were performed. Results D1 administration was less costly ($17,195 versus $17,681) and resulted in higher QOL (0.2298 quality adjusted life years (QALYs) versus 0.2288 QALYs) than D2. Results were sensitive to the risk of FN. D1 remained dominant or cost-effective (ICER less than $50,000/QALY) compared to D2 if the FN rate with D1 was assumed less than 14.5% (baseline estimate 10%). If the FN rate with D1 was assumed greater than or equal to 15%, D1 was not cost-effective compared to D2, with an ICER greater than $100,000/QALY. Findings are insensitive to variations in the modeled cost of treating FN, the additional cost of D2 injection, and the reduced QOL associated with treatment visits. Conclusion Administration of D1 pegfilgrastim is cost-effective in women with ovarian cancer who are treated with intermediate risk chemotherapy.

Balugrastim is a once-per-cycle, fixed-dose recombinant protein comprising human serum albumin and granulocyte colony-stimulating factor under development for prevention of severe neutropenia in cancer patients receiving myelosuppressive chemotherapy. This phase II, multicenter, active-controlled, dose-finding pilot study evaluated balugrastim safety and efficacy versus pegfilgrastim in breast cancer patients scheduled to receive myelosuppressive chemotherapy and investigated two doses with similar efficacy to pegfilgrastim for a subsequent phase III study. Patients received four cycles of doxorubicin/docetaxel chemotherapy and with each successive cycle were randomized sequentially to escalating doses of balugrastim [30 (n = 11), 40 (n = 21), or 50 mg (n = 20)] or a fixed dose of pegfilgrastim [6 mg (n = 26)] post-chemotherapy. Balugrastim doses were escalated as planned. The incidence of adverse events was similar among the balugrastim groups and between all balugrastim doses and pegfilgrastim. The most frequently reported adverse events were neutropenia, alopecia, and nausea. During cycle 1, severe neutropenia (absolute neutrophil count of

Hematopoietic stressors such as infection, bleeding, or toxic injury trigger a hematopoietic adaptation that sacrifices hematopoietic stem and progenitor cell (HSPC) quiescence to meet an urgent need for new blood cell production. Once the hematopoietic demands are adequately met, homeostasis must be restored. Transforming growth factor β (TGFβ) signaling is a central mediator mandating the return of HSPCs to quiescence after stress. Blockade of TGFβ signaling after hematopoietic stress delays the return of cycling HSPCs to quiescence and in so doing promotes hematopoietic stem cell (HSC) self-renewal and accelerates hematopoietic reconstitution. These findings open the door to new therapeutics that modulate the hematopoietic adaptation to stress. In this review, we will discuss the complex context-dependent activities of TGFβ in hematopoiesis and the potential benefits and limitations of using TGFβ pathway inhibitors to promote multilineage hematopoietic reconstitution after myelosuppressive chemotherapy.

The purpose of this study is to examine the real-world treatment patterns and outcomes of chemotherapy-induced (febrile) neutropenia (chemotherapy-induced (CIN)/febrile neutropenia (FN)) prophylaxis with biosimilar filgrastim (Zarzio®). MONITOR-GCSF is an international (12 countries), multi-center (140), prospective (max. six cycles), observational, open-label, pharmaco-epidemiologic study of cancer patients (n = 1447) treated with myelosuppressive chemotherapy across a total of 6,213 cycles and receiving prophylaxis with Zarzio®. Data were analyzed using both the patient and cycle as unit of analysis. Most (72.3 %) received primary prophylaxis; dosed mainly (53.2 %) at 30 MIU but differentiated by weight, chemotoxicity, and tumor type; and mainly (53.2 %) initiated in the 24–72h post-chemotherapy window but differentiated by prophylaxis type, tumor type, and chemotoxicity and for modal/median duration of 5 days. Relative to European Organisation for Research and Treatment of Cancer (EORTC) guidelines, 56.6 % were correctly prophylacted, 17.4 % under-prophylacted, and 26.0 % over-prophylacted. The following incidence rates were recorded: CIN grade 4 13.2 % of patients and 3.9 % of cycles, FN 5.9 % of patients and 1.4 % of cycles, CIN/FN-related hospitalizations 6.1 % of patients and 1.5 % of cycles, CIN/FN-related chemotherapy disturbances 9.5 % of patients and 2.8 % of cycles, and composite outcomes index 22.3 % of patients and 6.7 % of cycles. Rates varied by type of prophylaxis and tumor, chemotoxicity, initiation day, and prophylaxis duration. There were 1834 musculoskeletal events with 24.7 % of patients reporting bone pain of any grade (mostly mild to moderate), and 148 adverse drug reactions, including 4 serious, were recorded in 76 patients. The clinical and safety outcomes are well within the range of historically reported data for originator filgrastim underscoring the clinical effectiveness and safety of biosimilar filgrastim in daily clinical practice.

Generation of patient-derived, autologous dendritic cells (DCs) is a critical component of cancer immunotherapy with ex vivo-generated, tumor antigen-loaded DCs. An important factor in the ability to generate DCs is the potential impact of prior therapies on DC phenotype and function. We investigated the ability to generate DCs using cells harvested from pediatric patients with medulloblastoma for potential evaluation of DC-RNA based vaccination approach in this patient population. Cells harvested from medulloblastoma patient leukapheresis following induction chemotherapy and granulocyte colony stimulating factor mobilization were cryopreserved prior to use in DC generation. DCs were generated from the adherent CD14+ monocytes using standard procedures and analyzed for cell recovery, phenotype and function. To summarize, 4 out of 5 patients (80 %) had sufficient monocyte recovery to permit DC generation, and we were able to generate DCs from 3 out of these 4 patient samples (75 %). Overall, we successfully generated DCs that met phenotypic requisites for DC-based cancer therapy from 3 out of 5 (60 %) patient samples and met both phenotypic and functional requisites from 2 out of 5 (40 %) patient samples. This study highlights the potential to generate functional DCs for further clinical treatments from refractory patients that have been heavily pretreated with myelosuppressive chemotherapy. Here we demonstrate the utility of evaluating the effect of the currently employed standard-of-care therapies on the ex vivo generation of DCs for DC-based clinical studies in cancer patients.

The purpose of this study was to evaluate risk factors for bone pain in patients receiving myelosuppressive chemotherapy and pegfilgrastim. Individual patient data from 22 pegfilgrastim clinical trials were analyzed. Multivariable logistic regression models were used to evaluate risk factors associated with grade ≥2 bone pain and any grade bone pain in the first chemotherapy cycle and across cycles 1–6. Of the 1949 patients analyzed, 19 and 36 % had grade ≥2 and any grade bone pain, respectively, in cycle 1, and 28 and 51 % had grade ≥2 and any grade bone pain, respectively, across cycles 1–6. In cycle 1, history of bone pain (odds ratio (OR), 1.51; 95 % confidence interval (CI), 1.09–2.07) was associated with increased risk of grade ≥2 bone pain; age ≥65 years (versus

Treatment-associated neutropenia continues to represent the most common dose-limiting toxicity of cancer chemotherapy. It often leads to fever and infection, prompting hospitalization and occasionally resulting in serious morbidity, and even mortality, despite modern broad-spectrum antibiotic treatment and supportive care. Neutropenia and its complications may also lead to chemotherapy dose reductions, treatment delays, or early treatment termination, compromising disease control and the potential for cure. NCCN Clinical Practice Guidelines in Oncology recommend administration of primary prophylaxis with a myeloid growth factor in patients receiving regimens associated with a high risk for febrile neutropenia, and consideration of prophylaxis in patients receiving lower-risk regimens who have other risk factors that might place them at higher risk for febrile neutropenia. Although these agents have been shown to be effective and safe in numerous randomized controlled trials, they are expensive and contribute significantly to increasing health care costs. Regulatory agencies and guideline organizations do not currently address the issue of cost. However, with the relentless increase in health care use and current efforts to reform health care, it has become increasingly important to assess both the cost and the net benefit of interventions related to an episode of care in order to compare the overall value of therapeutic options. This article defines and discusses the intersection of quality, costs, and value in the context of prophylactic myeloid growth factor use in patients with cancer receiving myelosuppressive chemotherapy.

Myeloid colony-stimulating factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte–macrophage colony-stimulating factor) are commonly used in clinical practice for the prevention of anticancer chemotherapy-induced neutropenia and its potentially life-threatening complications. Pegfilgrastim is a novel recombinant human G-CSF pharmaceutically developed by covalent binding of a polyethylene glycol molecule to the N-terminal sequence of filgrastim. Due to its unique neutrophil-mediated clearance, pegfilgrastim can be administered once per chemotherapy cycle. Clinical trials have demonstrated that a single, fixed, subcutaneous dose of pegfilgrastim is comparable in safety and efficacy to daily injections of filgrastim for decreasing the incidence of infection following myelosuppressive chemotherapy in patients with cancer. Recent trials have been conducted to evaluate the use of pegfilgrastim in different clinical settings, including support of dose-dense regimens, mobilization and transplantation of hematopoietic stem cells.

Invasive fungal infections (IFIs) are now the main cause of death from infection in cases of allogeneic stem-cell transplantation and an important cause of morbidity and mortality in patients with haematological malignancies undergoing chemotherapy. Their prevention is one of the major objectives of anti-infective support programmes for onco-haematology patients. Fluconazole is safe and effective as prophylaxis for Candida infections in allogeneic stem-cell transplant (SCT) patients, although for non-SCT onco-haematology patients, its role has not been established, in spite of its very frequent use in clinical practice. After more than 10 years of massive use of fluconazole prophylaxis, there are several controversies in relation to its use. The emergence of resistant pathogens, the shift in the epidemiology of the main fungal pathogens, interactions among antifungal and non-antifungal drugs, organ toxicities and cost are some of the problematic issues, and similar problems should be expected with new drugs. Nowadays, the main IFI organisms in onco-haematology patients and the cause of the majority of fungal-related deaths are not Candida but Aspergillus species. Consequently, interest in fungal prophylaxis has moved from prevention of Candida infections to prevention of infections caused by Aspergillus , against which fluconazole has no activity. Itraconazole, administered as an oral solution or intravenously, but not as capsules, is an effective chemoprophylaxis for Aspergillus if the patient can tolerate the drug. New drugs, new prophylactic strategies and new forms of drug administration are under study and are reviewed in this article.

Objective. To provide oncology healthcare providers with information on current vaccine recommendations and discuss the proper timing of vaccination in relation to chemotherapy, to allow for an adequate, protective antibody response. Data sources. In this review, we have attempted to include all available literature as well as the current recommendations. The National Library of Medicine, PubMed online database was searched using the keywords: chemotherapy, influenza, vaccine, cancer, immunosuppression. In addition, the Center for Disease Control (CDC) guidelines were reviewed and incorporated into the recommendations. Data synthesis. There were several limitations to the literature available. To date, most of the literature was completed in the 1970s and 1980s, and definitions of protective immunity regarding influenza vaccines have changed over time, as well as improved study design. These studies have also been completed in a variety of disease states, hence, it is difficult to make comparisons between trials. The recommendations in this review are consistent with the current CDC Guidelines and, until further clinical trials are carried out, are the most conservative recommendations in favor of patient safety, health care costs, and resource utilization. Conclusion. Patients on cancer chemotherapy should receive vaccination at least 2 weeks before initiation of treatment. Providers should avoid administering vaccination during chemotherapy or active radiation treatment because of suboptimal responses to vaccines. Active immunization has been shown to confer protective immunity to several infections in cancer patients at similar rates to healthy individuals.

Purpose To evaluate the effects of once-weekly epoetin alfa (EPO) on health-related quality of life (HRQOL), hemoglobin (Hb), transfusions, and tolerability in children with cancer. Methods Anemic patients 5 years to 18 years of age receiving myelosuppressive chemotherapy for nonmyeloid malignancies, excluding brain tumors, received intravenous EPO 600 units/kg to 900 units/kg or placebo once-weekly for 16 weeks. Patients and parents completed the pediatric health-related quality-of-life generic scales (GS) and cancer-specific scales (CS). Results One hundred eleven patients received EPO and 111 patients received placebo. Mean final values for GS total score (P = .763 among patients; P = .219 among parents) and CS domain scores (P ≥ .238; P ≥ .081, respectively) were not significantly different between treatment groups. EPO-treated patients had greater increases in Hb overall (P = .002) and were more likely to be transfusion free after 4 weeks (38.7% v 22.5%; P = .010). Change in Hb was correlated with change in PedsQL-GCS total score in the EPO group (r = 0.242; P = .018), but was not in the placebo group (r = 0.086; P = .430). Adverse events were comparable between treatment groups. Conclusion This study confirmed the tolerability and hematologic benefits of once-weekly EPO in children with cancer. No significant difference in HRQOL was detected between treatment groups, but a significant positive correlation was observed between Hb changes and HRQOL changes in the EPO group. Additional studies are warranted to assess HRQOL when anemia is managed optimally in children with cancer.

The colony-stimulating factors (CSFs) are widely utilized to prevent neutropenic complications in both adults and children, but randomized controlled trials in the pediatric setting have reported varied results. A systematic review of the literature and meta-analysis were conducted to definitively assess the impact of prophylactic CSFs on the risk of febrile neutropenia (FN) in pediatric oncology patients.MEDLINE was searched and references hand-searched through July 2004 for randomized controlled trials of prophylactic G-CSF or GM-CSF in pediatric oncology patients. Objectives, outcomes, and quality of the 16 included studies were extracted by two reviewers. Weighted summary estimates of relative risks (RR) were calculated for FN and documented infection (DI). Mean differences in hospitalization, antibiotic use, and duration of neutropenia were calculated.FN occurred in 68% of 400 controls and 59% of 404 CSF patients. The estimated RR was 0.88 [0.81-0.97; (P=0.01)] favoring the CSFs for leukemia and high grade lymphoma studies and 0.71 [0.51-0.97; (P=0.03)] for solid tumor studies. DI occurred in 25% of controls and 20% of CSF patients for an estimated RR of 0.80 [0.61-1.06; (P=0.12)]. The mean decrease in duration of neutropenia was 3.5 days [2.2-4.7; (P0.0001)]. Mean decreases favoring CSF use were also observed for hospital stay of 1.7 days [0.9-2.5 (P0.01)] and antibiotic use of 2.0 days [0.4-3.6; P=0.02].Prophylactic CSFs significantly decrease the incidence of FN and the durations of severe neutropenia, hospitalization, and antibiotic use in pediatric cancer patients, but they do not significantly decrease documented infections.

Background: In clinical trials in patients receiving myelosuppressive chemotherapy, 10–11 days of prophylaxis with filgrastim has been found to reduce the incidence of febrile neutropenia. In clinical practice, however, many patients receive shorter courses of therapy, even though the effectiveness of this regimen is unknown. Objective: To examine the relationship between duration of filgrastim prophylaxis and risk of hospitalization in patients receiving chemotherapy for non–Hodgkin's lymphoma (NHL), breast cancer, or lung cancer. Methods: Using a large, automated, US healthcare claims database, we identified all adults who received chemotherapy for NHL, breast cancer, or lung cancer between 1998 and 2002. For these patients, we identified their first course of chemotherapy and each unique cycle within that course, We then focused attention on all patient cycles in which filgrastim was administered on or before cycle day 5 (filgrastim prophylaxis). Pooling all such cycles, we examined the relationship between duration of filgrastim prophylaxis and risk of hospitalization for neutropenia or infection and risk of hospitalization for any reason, using generalized estimating equations. Results: Mean ± SD duration of filgrastim prophylaxis was 6.5 ± 3.1 days across 332 cycles for 133 NHL patients, 6.1 ± 2.9 days across 482 cycles for 205 breast cancer patients, and 4.3 ± 3.1 days across 522 cycles for 260 lung cancer patients. In multivariate analyses, risk of hospitalization for neutropenia or infection was found to decline with each additional day of filgrastim prophylaxis for patients with NHL (OR 0.81; p = 0.003), breast cancer (OR 0.77; p = 0.001), and lung cancer (OR 0.91; p = 0.084). Risk reductions with each additional day of prophylaxis ranged from 15% to 19% for patients with NHL, 17% to 23% for those with breast cancer, and 8% to 9% for those with lung cancer. Similar reductions in risk were noted for all-cause hospitalization. Conclusions: Among patients with NHL, breast cancer, or lung cancer, shorter courses of filgrastim prophylaxis may increase the risk of hospitalization.

Patients with cancer receiving myelosuppressive chemotherapy frequently develop anaemia; platinum-based chemotherapy, in particular, leads to reduced production of the bone marrow-stimulating hormone erythropoietin. The European Cancer Anaemia Survey showed that many patients do not receive erythropoiesis-stimulating agent (ESA) therapy and highlighted the need for clear guidelines for the diagnosis and treatment of anaemia in cancer patients. In response to a fast-moving therapeutic environment and guidelines produced in the USA, the European Organisation for Research and Treatment of Cancer established an independent task force to develop evidence-based guidelines for the use of ESAs in European anaemic cancer patients that were first published in 2004. The guidelines recommend that, in patients receiving chemotherapy/radiotherapy, ESA therapy should be initiated at haemoglobin levels of 9-11 g/dL based on the severity of symptoms (target haemoglobin concentration: 12-13 g/dL) to improve quality of life and prevent the need for red blood cell transfusions. Treatment should be maintained as long as Hb levels remain

A phase III study of filgrastim as an adjunct to combination chemotherapy in previously untreated patients with limited- or extensive-stage small-cell lung cancer was conducted. This final analysis explores baseline factors that might predict febrile neutropenia and also reports the results of 463 open-label filgrastim cycles that were delivered after patients' initial episode of the primary endpoint, ie, febrile neutropenia.A total of 244 patients were randomized to receive placebo or filgrastim in/= 6 cycles of chemotherapy (cyclophosphamide/doxorubicin/etoposide).The cumulative percent of patients receiving filgrastim who experienced febrile neutropenia was approximately 50% lower than those given placebo (38% vs. 74%, respectively; P0.0001). Significant treatment-related reductions were also seen in the incidence and duration of grade 4 neutropenia. Cycle 1 displayed the highest incidence of neutropenia with or without fever and the longest duration of neutropenia relative to later cycles. Patients crossing over to open-label filgrastim from their blinded treatment assignment displayed event rates similar to those in the blinded filgrastim group. Patients who experienced febrile neutropenia in cycle 1 were at a significantly higher risk for subsequent events compared with those who were event-free in cycle 1. Women displayed a higher risk for febrile neutropenia than men, but no other baseline risk factors were detected.Given the high rate of febrile neutropenia in cycle 1 and the higher risk for subsequent events in patients with a cycle 1 event, we conclude that growth factor administration starting in cycle 1 should be considered for patients receiving moderately to highly myelosuppressive chemotherapy regimens.

Granulocyte colony-stimulating factor (CSF) and granulocyte-macrophage CSF are potent drugs used to increase neutrophil counts after myelosuppressive chemotherapy. However, in various indications, the use of CSFs has no clinical benefit with regard to morbidity or mortality from infectious complications, frequency of antibiotic use, or rate of hospitalization. Thus, the application of CSFs should be limited to indications with proven clinical benefits or evidence of cost-effectiveness. This review will provide an overview of the state-of-the-art use of CSFs in chemotherapy-associated neutropenia, transplantation, and bone marrow failure syndromes. In addition, recently developed drugs for accelerated hematopoietic recovery will be presented.

Study Objective. To evaluate the effects on efficacy and safety of a formulary change from granulocyte colony-stimulating factor (G-CSF) to granulocyte-macrophage CSF (GM-CSF). Design. Retrospective chart review. Setting. Single-center academic institution. Patients. Fifty-six patients aged 18 years or older with breast cancer, lung cancer, melanoma, Hodgkin's lymphoma, or non-Hodgkin's lymphoma who developed neutropenia within 4 weeks after treatment with myelo-suppressive chemotherapy and who had been given five or more doses of CSF as primary or secondary prophylaxis from January 1995–March 2002. Twenty-nine patients treated before January 2000 were given G-CSF; after the formulary change in January 2000, 27 patients were primarily given GM-CSF. Measurements and Main Results. The primary efficacy end point was time to an absolute neutrophil count of 1.5 times 103/mm3 or greater after treatment with CSF. Second and third efficacy end points, respectively, were frequency of febrile neutropenia and effect of CSF treatment on schedule and dose intensity of subsequent chemotherapy cycles. Primary and secondary safety end points, respectively, were frequency of adverse events and use of resources used to manage these events. The time to neutrophil recovery was similar with G-CSF and GM-CSF. Febrile neutropenia was more common in the patients given GM-CSF. Chemotherapy dose delays also were more common in patients treated with GM-CSF, as was the frequency of fever. Use of resources (platelet and red blood cell transfusions, intravenous antibiotics, and hospitalizations) was greater in the patients treated with GM-CSF. Conclusion. The formulary change to GM-CSF was associated with a higher frequency of febrile neutropenia, resultant chemotherapy dose delays, more adverse events, and greater use of resources to manage the adverse events. These results suggest that G-CSF and GM-CSF are not therapeutically equivalent, with G-CSF having a superior safety and efficacy profile for the prevention of chemotherapy-induced neutropenic events.

Thrombocytopenia remains the major dose-limiting toxicity of myelosuppressive chemotherapy in children with solid tumours. Recombinant human interleukin-11 (rhIL-11) has been approved by the Food and Drug Administration as treatment for adults with solid tumours and lymphomas with severe chemotherapy-induced thrombocytopenia. We conducted a phase I/II trial of rhIL-11 following ifosfamide, carboplatin and etoposide (ICE) chemotherapy in children with solid tumours or lymphomas. Patients received ifosfamide 1800 mg/m(2)/d for 5 d, carboplatin 400 mg/m(2)/d for 2 d and etoposide 100 mg/m(2)/d for 5 d with rhIL-11 subcutaneous (s.c.) at 25-125 microg/kg/d on days 6-33. Forty-seven patients with median age 10.5 years (range, 0.7-26 years) were studied. Median days to absolute neutrophil count >/=0.5 x 10(9)/l, platelet count >/=50 x 10(9)/l and platelet transfusions were 23, 18, 18, 16.5 and 18.5, 21, 20, 18 and 3, 3, 4, and 2 d at doses 25, 50, 75 and 100 Schulteg/kg respectively. There was a dose-dependent increase in C(max) (7.6-25.5 ng/ml), AUC(0-rho) (57-209 ng.h/ml) and T(1/2) (4-8.2 h) respectively. There was a 4% incidence of anti-IL-11 antibody formation. Clinically important adverse events to rhIL-11 were papilloedema and periosteal bone formation. In summary, rhIL-11 was well tolerated at doses of

Despite recent advances in the last decade, invasive fungal infections are still associated with a high morbidity and mortality. Invasive fungal infections constitute severe infectious complications in patients with hematological malignancies receiving myelosuppressive chemotherapy or sustained immunosuppression after allogeneic transplant regimens. Following a long period of stagnation, considerable progress has been made during the last 5 years in non-culture-based diagnostics and in the treatment of invasive fungal infections. This review highlights recent developments in the epidemiology, diagnosis, and treatment in the context of state-of-the-art management of invasive fungal infections in cancer patients.

Background It has long been known that patients both after myelosuppressive chemotherapy (ChTh) and after myeloablative bone marrow transplantation (BMT) show a long lasting impairment of cellular immune functions. However, recent reports have revealed that early after BMT a passing state of augmented immune responsiveness exists. Adoptive T cell therapy in this period of lymphopenia-induced (homeostatic) proliferation has shown better results than in steady state in murine studies. Procedure To determine whether also early after myelosuppressive ChTh enhanced immune responses can be found, we have determined proliferation of peripheral blood lymphocytes and calcium influx and performed immunophenotyping in pediatric patients recovering from myelosuppressive ChTh in comparison to immunoreconstituted patients late after BMT. Results The lymphocytes of the ChTh patients were found to proliferate vigorously in response to stimulation with a variety of antibodies and mitogens, while in the BMT patients any stimulation was severely reduced. The increase of intracellular calcium after stimulation was similar in both patient groups. ChTh patients showed an expansion of an activated “naive” phenotype (CD45RO− HLA-DR+) in both the CD4 and CD8 subsets. In contrast, BMT patients showed a prominent expansion of “memory type” T lymphocytes (CD45RO+ HLA-DR+). Conclusions Early after ChTh, a period of immunoaugmentation seems to exist. Whether this observation can be used clinically to increase cure rates remains to be elucidated. © 2004 Wiley-Liss, Inc.

Cytotoxic chemotherapy suppresses the hematopoietic system, impairing host protective mechanisms and limiting the doses of chemotherapy that can be tolerated. Neutropenia, the most serious hematologic toxicity, is associated with the risk of life-threatening infections as well as chemotherapy dose reductions and delays that may compromise treatment outcomes. The authors reviewed the recent literature to provide an update on research in chemotherapy-induced neutropenia and its complications and impact, and they discuss the implications of this work for improving the management of patients with cancer who are treated with myelosuppressive chemotherapy. Despite its importance as the primary dose-limiting toxicity of chemotherapy, much concerning neutropenia and its consequences and impact remains unknown. Recent surveys indicate that neutropenia remains a prevalent problem associated with substantial morbidity, mortality, and costs. Much research has sought to identify risk factors that may predispose patients to neutropenic complications, including febrile neutropenia, in an effort to predict better which patients are at risk and to use preventive strategies, such as prophylactic colony-stimulating factors, more cost-effectively. Neutropenic complications associated with myelosuppressive chemotherapy are a significant cause of morbidity and mortality, possibly compromised treatment outcomes, and excess healthcare costs. Research in quantifying the risk of neutropenic complications may make it possible in the near future to target patients at greater risk with appropriate preventive strategies, thereby maximizing the benefits and minimizing the costs.

BACKGROUND Mucositis is a common but poorly studied problem among patients with solid tumors. The authors examined the clinical and economic outcomes of oral and gastrointestinal (GI) mucositis among patients receiving myelosuppressive chemotherapy. METHODS A retrospective, random sample of 599 patients who developed chemotherapy-induced myelosuppression was followed for development of oral or GI mucositis and for development of subsequent episodes of bleeding or infection. Multilevel regression models of the risk of bleeding and infection were fit with chemotherapy cycles nested within patients. RESULTS Mucositis developed during 37% of 1236 cycles of chemotherapy. Episodes of bleeding were significantly more common during cycles with GI mucositis than during cycles without GI mucositis (13% vs. 8%; P = 0.04). Episodes of infection were significantly more common during cycles with mucositis (especially GI mucositis) than during cycles without mucositis (73% vs. 36%; P < 0.0001). The mean durations of hospitalization were 4 days, 6 days, and 12 days during cycles with no mucositis, oral mucositis, and GI mucositis, respectively. After accounting for the depth and duration of myelosuppression and for other predictive factors, GI mucositis was associated with both bleeding (odds ratio [OR], 2.0; P = 0.01) and infection (OR, 2.24; P < 0.0001), whereas oral mucositis was associated with infection only (OR, 2.4; P < 0.0001). CONCLUSIONS Mucositis was clinically and economically significant among patients with solid tumors who were receiving myelosuppressive chemotherapy. New preventive and therapeutic agents are needed. Cancer 2003;98:1531–9. © 2003 American Cancer Society. DOI 10.1002/cncr.11671

Anemia has been reported in approximately 40%-70% of patients with hematologic malignancies, with severity depending on the type and stage of disease and whether the patient has received myelosuppressive chemotherapy. Growing evidence supports the role of epoetin alfa in correcting anemia and improving quality of life (QOL) in patients with hematologic malignancies. Clinical practice guidelines recommend the use of epoetin alfa in patients with cancer-related anemia (including patients with hematologic malignancies) and hemoglobin levels ≤ 10 g/dL. Epoetin alfa treatment is optional for patients with cancer-related anemia and hemoglobin levels > 10 g/dL and < 12 g/dL, depending on clinical circumstances. A prospective, open-label, randomized trial evaluating hematologic response, transfusion use, and QOL after immediate or delayed epoetin alfa treatment in mildly anemic patients (hemoglobin ≤ 12 g/dL) undergoing chemotherapy for chronic lymphocytic leukemia, multiple myeloma, or lymphoma was recently completed. Study objectives included determining any correlation between changes in hemoglobin level and QOL and assessing any correlation between QOL measures and health care resource use. Interim results suggest that epoetin alfa treatment in patients with hematologic cancers and hemoglobin ≤ 12 g/dL who are receiving chemotherapy increases hemoglobin, functional capacity, well-being, work and productivity, and health resource use. Further evaluation of alternative epoetin alfa dosing schedules and use of epoetin alfa in treating anemia in patients with specific hematologic malignancies is ongoing.

Haematological malignancy is the major indication for allogenic and autogenic bone marrow transplantation. Patients with certain solid tumours (e.g. small-cell lung cancer, breast or ovarian adenocarcinoma, germ cell tumours) may also undergo autografts, but this is usually in the setting of a clinical trial. The prognosis after bone marrow transplantation has been substantially improved by progress made in the management of infectious complications and immunosuppression (Rowe et al, 1994). Unfortunately, many of the drugs used (antibiotics, cyclosporine, etc.) have adverse effects, particularly metabolic and gastrointestinal effects. This is in addition to the side-effects of the conditioning regimen (total body irradiation, myelosuppressive chemotherapy), any graft complications (graft-versus-host (GVH) disease and veno-occlusive disease) and disease response (tumour lysis syndrome). Gastrointestinal and infectious complications are frequent and often lead to a significant reduction in oral food intake. In this situation, a protein-calorie deficiency can occur rapidly and this may continue even after recovery of the bone marrow.

OBJECTIVE: To discuss clinical data on the utility of 2 colony-stimulating factors (CSFs), filgrastim and pegfilgrastim, in reducing the risk and incidence of neutropenic complications with chemotherapy. DATA SOURCES: This article reviews the data from the clinical studies for both pegfilgrastim and filgrastim. Additionally, data from large, population-based retrospective analyses on the clinical and economic consequences of chemotherapy-induced neutropenia (CIN) are reviewed. CONCLUSIONS: CIN remains an undertreated condition despite the evidence of its danger. Pivotal trials show that CSFs like pegfilgrastim and filgrastim are safe and effective in reducing both the incidence and duration of CIN and febrile neutropenia in patients who have been treated with myelosuppressive chemotherapy. Approximately 11 daily injections of filgrastim per chemotherapy cycle are required to achieve this clinical end point. Pegfilgrastim provides all the clinical benefits of daily filgrastim for managing CIN with a single dose per chemotherapy cycle.

Bone pain is a common side effect of treatment with filgrastim. Pegfilgrastim is a pegylated long-acting analogue of filgrastim that is administered once per chemotherapy cycle. The profile of prospectively defined, patient-reported bone pain judged by the investigators as related to study drug was analyzed retrospectively for each drug using data from two comparable phase III trials. These multicenter, randomized, double-blind, noninferiority trials compared once-per-cycle pegfilgrastim (6 mg, study 1 or 100 microg/kg, study 2) to daily filgrastim 5 microg/kg in patients with stage II-IV breast cancer undergoing multiple cycles of myelosuppressive chemotherapy (doxorubicin/docetaxel). Subcutaneous once-per-cycle pegfilgrastim 6-mg and 100-microg/kg doses were administered to 76 and 150 patients, respectively; subcutaneous daily filgrastim 5 microg/kg was administered to a total of 227 patients. Because bone pain in study 1 was higher (P = 0.044) in every cycle compared with study 2, all analyses were performed separately for each study. No statistically significant differences in incidence, severity, or duration were observed between patients receiving either once-per-cycle pegfilgrastim or daily filgrastim in either study. Bone pain incidence and severity were significantly greater (P0.001) in cycle 1 of both studies compared with later cycles. Among patients with bone pain, a trend towards earlier onset with pegfilgrastim was observed but was not associated with increased bone pain severity or duration. In patients who received a fixed 6-mg dose of pegfilgrastim, the overall bone pain incidence was similar when analyzed by body weight (60 kg, 60-100 kg,100 kg). No patients were withdrawn from either study for bone pain.

Recombinant human eythropoietin (rh-epo) is a well established treatment for many kinds of anemia including the anemia of cancer with or without myelosuppressive chemotherapy. This review considers the effects of rh-epo in humans, tumour-bearing and healthy experimental animals treated with cisplatin with or without rh-epo, and proposes that the ability of rh-epo to improve the quality of life in cancer patients may also be due to interference with the prostaglandin pathways.

Some malignant tumors in childhood require high-dose chemotherapy with stem cell support to achieve a cure. In patients heavily pretreated with myelosuppressive chemotherapy or irradiation, granulocyte colony-stimulating factor (G-CSF) may fail to mobilize stem cells from the bone marrow. Based on the experience with lymphoma and myeloma patients in whom peripheral blood-derived stem cell (PBSC) collection following mobilization with G-CSF failed, we successfully employed plerixafor in a 14-year-old female diagnosed with Ewing's sarcoma in early relapse treated with three lines of chemotherapy in whom PBSC could not be mobilized using either G-CSF alone or G-CSF following chemotherapy. No side effects were observed. Plerixafor may be an effective and safe agent for stem cell collection in pediatric patients with solid tumors, although new studies addressed to evaluate its effectiveness and safety are needed. J. Clin. Apheresis 27:260–262, 2012. © 2012 Wiley Periodicals, Inc.

Severe neutropenia following cytotoxic, anti-cancer chemotherapy is well-known to be associated with an increased risk of infections that may be life-threatening, particularly if not treated immediately. Consequently, serial measurements of neutrophil counts in peripheral blood are done routinely following the administration of high-dose myelosuppressive chemotherapy in order to monitor the onset, severity, and duration of iatrogenic neutropenia. We have studied a non-invasive method of quantifying neutrophils recoverable from the oral mucosa, a normal tissue site of neutrophil turnover, as an alternative approach for monitoring severe, chemotherapy-induced neutropenia. This method is based on the quantification of fluorochrome-stained neutrophils present in timed mouthwash specimens. Blood neutrophil (ANC) and mucosal neutrophil counts (MNC) were measured repeatedly in 23 patients who had been treated with dose-intensive chemotherapy for a variety of indications. All 23 patients developed profound neutropenia (ANC 101°F) during the 2 weeks following treatment. Nadirs of neutropenia defined by MNC were significantly less prolonged than those defined by the ANC. Furthermore, the onset and resolution of neutropenic fever coincided more precisely with nadirs of neutropenia defined by the MNC than with those defined by the ANC. Our findings indicate that oral mucosal neutrophil counts predict the timing of clinical events associated with neutropenia (e.g., the onset and resolution of fever) with significantly greater accuracy than blood neutrophil counts. Am. J. Hematol. 72:13–19, 2003. © 2002 Wiley-Liss, Inc.

Acute myeloid leukemia (AML) in older adults is a biologically and clinically distinct entity. Based on analysis of cytogenetic and molecular data, it is known that leukemic cells in older patients are intrinsically resistant to standard chemotherapy. Due to comorbid disease and impaired bone marrow stem cell reserve, older adults tolerate myelosuppressive chemotherapy poorly, with a treatment-related mortality rate of 25 percent. About 35 percent of adults under age 40 are cured, but the complete remission rate (likelihood of temporary disease eradication) is 45 percent in those over age 60, considerably lower than the 75% rate among younger patients, and the possibility of long-term disease free survival is 20 percent in those achieving remission or less than 10 percent overall. Standard allogeneic bone marrow transplantation is too dangerous to be considered as a means to eradicate minimal residual disease after remission is obtained and myelointensive chemotherapy is not a beneficial post-remission strategy in this age cohort. These disappointing results call for more effective and less toxic therapeutic options. Advances in our understanding of the pathophysiology of AML and promising early clinical data suggest that the era of truly targeted therapy in this difficult disease may soon be a reality.

In children and adolescents, prophylactic application of G-CSF after myelosuppressive chemotherapy reduces the duration of neutropenia, of hospitalization, and of parenteral antibiotic treatment. In acute lymphoblastic leukemia, non-Hodgkin lymphoma, and solid tumors, G-CSF support allows dose intensification of chemotherapy. On the other hand, each G-CSF injection causes pain and costs. We set up the hypothesis that besides strategies as restricted indications, delayed start, lower doses, and stringent rules for discontinuation, individualized timing of blood count might optimize G-CSF prophylaxis. We randomized 64 cycles of G-CSF prophylaxis in eight children and adolescents being treated for acute lymphoblastic leukemia or solid tumors to standard twice a week or to individually timed blood counts. Primary study endpoints were the numbers of G-CSF doses and of blood counts, and the total costs of G-CSF support. Per cycle, individual timing of blood count resulted in a median of one G-CSF injection fewer [estimated population median (EPM) 1.40, 95% confidence interval (CI) 0.57-2.20] and one blood count fewer (EPM 1.00, 95% CI 0.74-1.33). The total costs of G-CSF support and of blood counts were thereby reduced by a median of US $ 152 per cycle (EPM 191, 95% CI 97-318). The results of this study suggest that individual timing of blood counts during prophylactic G-CSF support in children and adolescents undergoing chemotherapy for malignant disease can significantly reduce the number of injections and blood counts performed, thus resulting in less pain and lower costs. These findings need confirmation in a larger randomized trial.

Objective. Hematopoietic stem and progenitor cells normally reside in the bone marrow but can be mobilized into the peripheral blood following treatment with granulocyte colony-stimulating factor (G-CSF) or myelosuppressive chemotherapy. Although the number of transplants performed with mobilized blood currently exceeds those performed with bone marrow, little is known of the molecular mechanisms responsible for this phenomenon. We sought to determine whether mobilization induced by G-CSF or chemotherapy was triggered by common or distinct mechanisms. Methods. Balb/c mice were mobilized with either G-CSF alone, cyclophosphamide alone, or the combination of both agents. Spleens, peripheral blood, bone marrow extracellular fluids, and cells were taken at different time points and analyzed for the expression of VCAM-1, the number of peripheral blood progenitor cells, concentration of neutrophil proteases, and number of granulocytes. Results. Administration of either G-CSF or the myelosuppressive agent cyclophosphamide results in a sharp reduction of VCAM-1/CD106 expression in the bone marrow that coincides with the accumulation of granulocytic precursors and release of active neutrophil proteases neutrophil elastase and cathepsin G that directly cleave VCAM-1/CD106 in vitro. These events follow precisely the kinetics of hematopoietic progenitor cell mobilization into the peripheral blood. Conclusion. We have identified a commonality of events during mobilization induced by either G-CSF or chemotherapy, which include the accumulation in the bone marrow of active neutrophil proteases that directly cleave VCAM-1 and lead to the sharp reduction of VCAM-1 expression in this tissue.

The association of neutropenia and infection continues to be a major cause of morbidity and mortality in cancer patients receiving myelosuppressive chemotherapy. Prompt hospitalization and initiation of empirical intravenous broad-spectrum antibiotics has been the standard of care during the past three decades. Recently, risk-assessment models have been developed that allow the identification of febrile neutropenic patients that are at low risk for medical complications and mortality. New treatment strategies are being evaluated in this low-risk patient population to safely reduce toxicity, decrease costs, and improve quality of life. These include early shift from intravenous therapy to oral antibiotics, immediate initiation of oral empiric treatment, early hospital discharge, or outpatient care. A risk-based approach should also be applied to the use of colony-stimulating factors in this setting. Growth factors should not be routinely administered to neutropenic patients with uncomplicated febrile episodes. However, recent data support their use in populations with high-risk neutropenic fever.