Patients Receiving Chemotherapy Regimens Research Articles

Attitudes of physicians toward assessing risk and using granulocyte colony-stimulating factor as primary prophylaxis in patients receiving chemotherapy associated with an intermediate risk of febrile neutropenia.

Febrile neutropenia (FN) is a potentially fatal complication of chemotherapy. This prospective, observational study describes physicians' approaches toward assessing FN risk in patients receiving chemotherapy regimens with an intermediate (10-20%) FN risk. In the baseline investigator assessment, physicians selected factors considered important when assessing overall FN risk and deciding on granulocyte colony-stimulating factor (G-CSF) primary prophylaxis (PP). Physicians then completed patient assessments using the same lists of factors. The final FN risk scores and whether G-CSF PP was planned were reported. The final analysis included 165 physicians and 944 patients. The most frequently considered factor in both assessments was chemotherapy agents in the backbone (88% of investigator and 93% of patient assessments). History of FN (83%), baseline laboratory values (76%) and age (73%) were commonly selected at baseline, whereas tumor type (72%), guidelines (62%) and tumor stage (43%) were selected most during patient assessments. Median investigator-reported FN risk threshold for G-CSF PP was 20% (range 10-85%). G-CSF PP was planned in 82% of patients with an FN risk at or above this threshold; therefore, almost one-fifth of qualifying patients would not receive G-CSF PP. Physicians generally follow guidelines, but also consider individual patient characteristics when assessing FN risk and deciding on G-CSF PP. A standardized FN risk assessment may optimize the use of G-CSF PP, which may minimize the incidence of FN in patients undergoing chemotherapy with an intermediate FN risk. ClinicalTrials.gov Identifier: NCT01813721.

Importance of Risk Factors for Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified as High-Risk in Guidelines for Myeloid Growth Factor Use.

Clinical practice guidelines recommend prophylaxis in patients with cancer receiving a colony-stimulating factor (CSF) when the risk of febrile neutropenia (FN) is high (>20%). For patients receiving chemotherapy regimens not documented as high-risk, the decision regarding CSF prophylaxis use can be challenging, because some patients may be at high risk based on a combination of the regimen and individual risk factors. A retrospective cohort design and US private health care claims data were used. Study subjects received chemotherapy regimens classified as "low" or "intermediate," or unclassified, in terms of FN risk, and were stratified by cancer and regimen. For each subject, the first chemotherapy course, and each cycle and FN episode within the course, were identified. FN incidence proportions were estimated by the presence and number of risk factors and chronic comorbidities. Across the 17 tumor/regimen combinations considered (n=160,304 in total), 74% to 98% of patients had 1 or more risk factor for FN and 41% to 89% had 2 or more. Among patients with 1 or more risk factor, FN incidence ranged from 7.2% to 29.0% across regimens, and the relative risk of FN (vs those without risk factors) ranged from 1.1 (95% CI, 0.8-1.3) to 2.2 (95% CI, 1.5-3.0). FN incidence increased in a graded and monotonic fashion with the number of risk factors and comorbidities. In this retrospective evaluation of patients with cancer receiving chemotherapy regimens not classified as high-risk for FN in US clinical practice, most patients had 1 or more FN risk factor and many had 2 or more. FN incidence was found to be elevated in these patients, especially those with multiple risk factors.

Incidence of Febrile Neutropenia Among Patients Receiving Chemotherapy Regimens Not Classified As High-Risk in Guidelines for Myeloid Growth Factor Use: Importance of “Risk Factor Stacking”

Background: Clinical practice guidelines recommend primary prophylactic colony-stimulating factor (CSF) when risk of febrile neutropenia (FN) is ≥20%. Evaluating FN risk among patients who receive regimens that are not documented as high risk in guidelines can be challenging, as some patients may be at a high risk based on a combination of the regimen and their risk factors.Methods: A retrospective cohort design and data from two US private healthcare claims repositories (2003-2012) were employed. The study population comprised cancer patients aged ≥18 years who initiated a course of chemotherapy with a regimen classified as “low” or “intermediate”, or that was unclassified, in terms of FN risk based on guidelines for CSF use. For each subject, the first qualifying chemotherapy course, and each cycle and FN episode within the course, was identified; use of CSF prophylaxis also was identified. FN was ascertained using diagnosis codes for neutropenia, fever, and/or infection; for FN requiring outpatient care only, receipt of intravenous antimicrobials also was required. FN incidence proportion was evaluated during the course within cohorts stratified by tumor type and regimen, for all patients in each cohort and by FN risk factor. Risk factors documented in guidelines and the published literature, and listed in the Table herein were evaluated during the 12-month pre-chemotherapy period. Unadjusted relative risks of FN for patients with versus without risk factors, and by the number of risk factors (i.e., “risk factor stacking”), were estimated. Only results for the five most frequently observed tumor/regimen combinations are reported herein.Results: Among patients with one of the five most frequently observed tumor/regimen combinations (n=84,252), 74-97% had ≥1 risk factor for FN and 42-88% had ≥2 (Table). Among patients with ≥1 risk factor, FN incidence ranged from 11-25% (relative risk vs. those without risk factors, 1.4-2.1), and increased in a graded and monotonic fashion with the number of risk factors present (Figure).Conclusion: In this retrospective evaluation of nearly 85,000 cancer patients receiving chemotherapy regimens not classified as high-risk for FN in US clinical practice, the large majority had at least one risk factor for FN and many had two or more. FN incidence was found to be markedly elevated in these patients, especially those with multiple risk factors (i.e., “risk factor stacking”). [Display omitted] [Display omitted] DisclosuresWeycker:Amgen: Research Funding. Li:Amgen: Employment, Equity Ownership. Barron:Amgen: Employment, Equity Ownership. Wu:Amgen: Research Funding. Morrow:Amgen: Employment, Equity Ownership. Xu:Amgen: Employment, Equity Ownership. Reiner:Amgen: Employment, Equity Ownership. Garcia:Amgen: Employment, Equity Ownership. Mhatre:Amgen: Employment. Lyman:Amgen: Research Funding.

The Role of Microenvironment Expression of Pd-1 Ligands and Chemokines in Clinical Outcome of Hodgkin'S Lymphoma

ABSTRACT Aim: Classical Hodgkin's lymphoma (cHL) is characterized by only few malignant cells and an abundance of inflammatory cells. cHL infiltrating cells produce cytokines and growth factors that provide essential stimulatory signals for survival and proliferation of Hodgkin and Reed–Sternberg (HRS) cells. Moreover, clinical behaviour of cHL may be directly regulated by the cross-talk between HRS cells and other cells in their microenvironment. The aim of our study was to estimate the role of microenvironment expression of PD-1 ligands and chemokines in clinical outcome of cHL. Methods: The case group comprised 49 patients with cHL (stage IIA: 23, IIB: 3, III-IV: 23). The patients received chemotherapy regimens (ABVD or BEACOPP 14/esc) and radiotherapy by indications. cHL specimens were obtained from lymph node biopsies of patients at diagnosis. PD-L1, PD-L2, MIP-1a, RANTES mRNA expression levels were analyzed in fresh tissue specimens using real-time RT-PCR. Results: We observed that 26.5 % (13/49) of cHL cases were PD-L1 negative, 16.3 % (8/49) - RANTES negative and 14.3 % (7/49) – both PD-L1 and RANTES negative. MIP-1a and RANTES expression levels were slightly higher in mixed cellularity cHL (p = 0.15), whereas PD-L1 – in nodular sclerosis cHL and advanced stages of disease (p = 0.19). PD-L2 expression level was independent of histological cHL variant or disease stage. All cases with the absence of both PD-L1 and RANTES markers had a complete response to the therapy and long-term remission. For the patients with increasing of RANTES/MIP-1a rate, a trend for a higher risk of relapse was observed (P = 0.09). ROC analysis revealed that PD-L1 expression level in tumor is an important marker which is associated with clinical outcome of cHL patients (Se = 87.5 %; Sp = 64.5 %; AUC = 0.75; p = 0.002). High PD-L1 expression was associated with reduced progression-free survival (PFS) in cHL patients. The 2-year PFS rate for cHL patients with high PD-L1 expression was 47 % compared to 95 % for low or absent of PD-L1 expression (p = 0.04). Conclusions: Our results suggest that tumor microenvironment play an important role in clinical behavior of cHL. PD-L1 expression level can be used as a marker of prognosis in patients with cHL and represent an attractive target for a cHL immunotherapy in patients with poor outcome. Disclosure: All authors have declared no conflicts of interest.

White blood cell growth factor use in an outpatient oncology clinic: Lessons and opportunities learned

The increased use and high cost associated with white blood cell growth factors at our outpatient oncology clinic has prompted this evaluation. The objectives of this study were to categorize the indication for use of pegfilgrastim and filgrastim; evaluate the administration of these white blood cell growth factors; identify opportunities for cost savings; and identify ways to increase prescriber adherence to evidence-based practice guidelines. This medication use evaluation study involved retrospective data collection from patient medical records. Adult oncology patients treated in the outpatient oncology clinic who received filgrastim or pegfilgrastim were identified and included in this study. Computerized patient records were used to collect data on patient demographics, risk factors for febrile neutropenia, prescribing patterns for filgrastim and pegfilgrastim, and chemotherapy regimens. The number of pegfilgrastim and filgrastim doses were predominately used for primary prophylaxis following chemotherapy treatment. Of the 234 total doses of pegfilgrastim used in the setting of primary prophylaxis, 28 (12%), 134 (57%), and 72 (31%) doses were given to patients receiving chemotherapy regimens associated with a high risk (>20%), intermediate risk (10-20%), and low risk (<10%) of febrile neutropenia, respectively. The total number of pegfilgrastim doses used in secondary prophylaxis was 78; 20 (26%) and 58 (74%) of these doses were given to patients receiving chemotherapy regimens associated with an intermediate risk and low risk of febrile neutropenia, respectively. This study revealed a significant portion of prescribed growth factor use that was not in accordance with clinical practice guidelines.

Can treatment with Cocculine improve the control of chemotherapy-induced emesis in early breast cancer patients? A randomized, multi-centered, double-blind, placebo-controlled Phase III trial

BackgroundChemotherapy induced nausea and vomiting (CINV) remains a major problem that seriously impairs the quality of life (QoL) in cancer patients receiving chemotherapy regimens. Complementary medicines, including homeopathy, are used by many patients with cancer, usually alongside with conventional treatment. A randomized, placebo-controlled Phase III study was conducted to evaluate the efficacy of a complex homeopathic medicine, Cocculine, in the control of CINV in non-metastatic breast cancer patients treated by standard chemotherapy regimens.MethodsChemotherapy-naïve patients with non-metastatic breast cancer scheduled to receive 6 cycles of chemotherapy including at least three initial cycles of FAC 50, FEC 100 or TAC were randomized to receive standard anti-emetic treatment plus either a complex homeopathic remedy (Cocculine, registered in France for treatment of nausea and travel sickness) or the matching placebo (NCT00409071 clinicaltrials.gov). The primary endpoint was nausea score measured after the 1st chemotherapy course using the FLIE questionnaire (Functional Living Index for Emesis) with 5-day recall. Secondary endpoints were: vomiting measured by the FLIE score, nausea and vomiting measured by patient self-evaluation (EVA) and investigator recording (NCI-CTC AE V3.0) and treatment compliance.ResultsFrom September 2005 to January 2008, 431 patients were randomized: 214 to Cocculine (C) and 217 to placebo (P). Patient characteristics were well-balanced between the 2 arms. Overall, compliance to study treatments was excellent and similar between the 2 arms. A total of 205 patients (50.9%; 103 patients in the placebo and 102 in the homeopathy arms) had nausea FLIE scores > 6 indicative of no impact of nausea on quality of life during the 1st chemotherapy course. There was no difference between the 2 arms when primary endpoint analysis was performed by chemotherapy stratum; or in the subgroup of patients with susceptibility to nausea and vomiting before inclusion. In addition, nausea, vomiting and global emesis FLIE scores were not statistically different at any time between the two study arms. The frequencies of severe (Grade ≥ 2) nausea and vomiting were low in our study (nausea: P: 17.6% vs C: 15.7%, p=0.62; vomiting: P: 10.8% vs C: 12.0%, p=0.72 during the first course).ConclusionThis double-blinded, placebo-controlled, randomised Phase III study showed that adding a complex homeopathic medicine (Cocculine) to standard anti-emetic prophylaxis does not improve the control of CINV in early breast cancer patients.

Individualized chemotherapy in advanced NSCLC patients based on mRNA levels of BRCA1 and RRM1

Experimental evidence suggests that the overexpression of breast cancer-specific tumor suppressor protein 1 (BRCA1) gene enhances sensitivity to docetaxel and resistance to cisplatin and ribonucleotide reductase M1 (RRM1) gene overexpression enhances resistance to gemcitabine. To further examine the effect of BRCA1 and RRM1 mRNA levels on outcome in advanced non-small cell lung cancer (NSCLC), we performed this non-randomized phase II clinical trial which tested the hypothesis that customized therapy would confer improved outcome over non-customized therapy. RNA was isolated from fresh tumor tissue. Patients received chemotherapy regimen based on their BRCA1 and RRM1 mRNA levels: both low-cisplatin plus gemcitabine (GP); both high-vinorelbine plus cisplatin (NP); BRCA1 low and RRM1 high-cisplatin plus docetaxel (TP); BRCA1 high and RRM1 low-vinorelbine plus gemcitabine (GN). From Dec 2005 to Nov 2008, 94 metastatic and locally advanced NSCLC patients from our institute were enrolled in this study. The median age was 58 years old. Among them, 21 patients received GP, 30 patients received TP and 43 patients received NP chemotherapy. GP group had a higher response rate, and longer median time to progression (TTP) and median overall survival (OS) time than the other 2 groups. The response rates in the GP, TP and NP groups were 42.9%, 36.7% and 27.9%, respectively (P=0.568). The median TTP was 5.6, 5.0, 4.8 months (P=0.975), respectively, and the median OS time was 12.5, 11.0, 9.7 months (P=0.808), respectively. Chemotherapy customized according to BRCA1 and RRM1 expression levels is associated with higher response rate and longer TTP and OS time in the GP group. This suggests that BRCA1 and RRM1 mRNA levels could be used as biomarkers in individual therapy in NSCLC.

Achievement of Complete Response Is Important for Longer Overall Survival in Patients with Newly Diagnosed Myeloma: A Single-Institutional Study

Abstract 5115 INTRODUCTION.Even with the introduction of novel therapeutic agents, including thalidomide, bortezomib, and lenalidomide, multiple myeloma (MM) is an incurable disease. Deeper responses, such as complete response (CR) and very good partial response (VGPR), are major goals of treatment to obtain long-term overall response (OS) and progression-free response (PSF) in patients with MM. Recent large randomized retrospective studies also suggested improved OS and PFS in patients who achieved deeper responses. However, the prognostic impact of achieving CR or VGPR remains controversial. In addition, these studies included selected patients that may not be representative of the general population. Therefore, we analyzed cases in our database to evaluate the impact of treatment response on the outcome of consecutive patients with symptomatic MM who were treated with chemotherapeutic regimens containing novel agents over the past 6 years at our institution in Kamogawa City, Japan. PATIENTS AND METHODS.We included 97 consecutive patients treated at our institution between April 2005 and May 2011. The study population consisted of 56 male and 41 female patients with a median age of 70 years old (range: 45 −90). Due to the rapid changes in treatment modality and government approval of novel agents in myeloma during this period, initial treatment could not be uniformly categorized, but all patients received chemotherapy regimens containing at least one novel agent, including thalidomide, bortezomib, and lenalidomide. These patients were thought to be more representative of the general myeloma population. Seventy-seven (79.4%), 27 (38.6%), and 55 (56.7%) patients received bortezomib-, lenalidomide-, and thalidomide-containing regimens, respectively. Treatment responses were assessed using the International Myeloma Working Group (IMWG) criteria with minor modifications, and the best response to treatment during the course of disease was evaluated. Immunofixation test and serum free light chain measurements were performed for confirmation of CR and stringent CR. OS was calculated from the time of diagnosis until the date of death from any cause or the date on which the patient was last known to be alive. Univariate and multivariate analyses were performed for the following variables: age at diagnosis, International Staging System (ISS), and best response achieved. RESULT.The median age of patients was 71 y.o. (range: 49 −90 y.o.), and the male to female ratio was 56:41. The best responses to treatment were as follows: CR was obtained in 19 cases (19.6%), VGPR in 29 (29.9%), partial response (PR) in 34 (35.0%), and stable disease (SD) or less in 15 (15.4%). Baseline characteristics according to best response achieved in patients who achieved CR, VGPR, PR, and SD or less were similar among the patients ≥70 y.o. vs. ≤70 y.o. Patients’ age has no impact on the response to treatment. With a median follow-up of 25 months, Kaplan–Meier estimated 3-year and 5-year overall survival (OS) rates were 67.2% and 35.0%, respectively. The 3- and 5-year OS were 100% in patients with CR, which were significantly superior in patients with VGPR (3-y 70%, 5-y 55.0%) and PR (3-y 60%, 5-y 23.0%). The 3- and 5-year OS were not significantly different between patients with VGPR and PR. Normalization of FLC kappa/Lambda ratio was observed in 15 of 19 (80%) patients with CR, 15 of 29 (51%) with VGPR, 4 of 34 (6.6%) in PR, and in none of 15 (0%) in SD or less. Patients who showed normalization of FLC kappa/Lambda ratio had significant OS benefit compared to those who did not. Proportional hazard Cox models showed that patients with ISS stage I/II had better 5-year OS rate compared to patients with stage III (51%; 20%, P = 0.005). However, there was no association between ISS stage and achievement of CR. CONCLUSION.The results of the present study highlighted the importance of achieving CR, not PR or VGPR, and normalization of FLC kappa/Lambda ratio for obtaining long-term OS in patients with MM regardless of age or ISS stage. Disclosures:No relevant conflicts of interest to declare.

Re: Personalized Medicine and Cancer Supportive Care: Appropriate Use of Colony-Stimulating Factor Support of Chemotherapy

Re: Personalized Medicine and Cancer Supportive Care: Appropriate Use of Colony-Stimulating Factor Support of Chemotherapy

Prediction of venous thromboembolism in ambulatory patients with cancer receiving chemotherapy: An expanded thromboembolic risk score model.

e19551 Background: Cancer and chemotherapy are well recognized risk factors for thromboembolic events (TEs). Nadroparin has been demonstrated to reduce the incidence of TEs by about 50% in cancer outpatients receiving chemotherapy. Patients receiving regimens containing cisplatin, carboplatin or gemcitabine and their combination have the highest risk of TEs. Khorana and colleagues have validated a score (KS) to identify the risk of TEs in cancer patients, stratifying them according to five variables (site of cancer, platelet count, haemoglobin level, leukocyte count and body mass index). Patients with a score ≥ 3 are at high risk to develop TEs. Methods: In our analysis we have expanded the KS by incorporating the chemotherapy variable: for patients receiving chemotherapy regimens containing cisplatin or carboplatin or gemcitabine 1 point has been added to the score; while regimen containing platinum compound plus gemcitabine 2 points. The aim of this post-hoc analysis was to evaluate the ability of this expanded Khorana risk score (ExKS) to identify high risk patients among the PROTECHT trial (NCT 00951574) population. A receiver operating characteristic (ROC) curve has been used to assess the accuracy of KS and ExKS. Results: Among the 1150 evaluable patients: 381 were allocated in the placebo arm and for 378 of them an evaluation of KS and ExKS has been performed: 11.1% (42/378) and 32.8% (124/378) were at high risk of TEs in the KS and ExKS, respectively. In the study population a total of 15 TEs has been reported. 33.3% (5/15) and 66.7% (10/15) of TEs occurred in the high risk patients according to KS and ExKS, respectively. A ROC curve analysis has been performed to evaluate the predictability of the ExKS respect to KS. The Area under the ROC Curve, which reflects the predictive value of the scores, was larger with ExKS in comparison with KS (0.70 and 0.65 respectively) Conclusions: ExKS could have a higher predictability to identify high risk patients for TEs compared to KS in the PROTECHT study. A prospective study is warranted to validate the score

The chemotherapy metabolite acrolein upregulates thrombin generation and impairs the protein C anticoagulant pathway in animal‐based and cell‐based models

Thrombosis is a common complication in cancer patients receiving chemotherapy regimens that include cyclophosphamide. However, the mechanisms by which these agents increase this risk are largely uncharacterized. To examine the effects of cyclophosphamide and its metabolite acrolein on procoagulant and anticoagulant pathways in both cell-based and animal-based models. Thrombin and activated protein C (APC) generation were measured in defibrinated plasma exposed to acrolein-treated endothelial and smooth muscle cells. Tissue factor (TF) activity was measured on acrolein-treated cells. Cell surface levels of phosphatidylserine, TF, endothelial protein C receptor and thrombomodulin were measured. Healthy BALB/c mice received injections of saline (control), acrolein, or cyclophosphamide; blood was collected, and plasma thrombin-antithrombin (TAT) complex, protein C and APC levels were analyzed. Exposure of acrolein-treated endothelial and smooth muscle cells to defibrinated plasma increased thrombin generation in the plasma. This was associated with enhanced phosphatidylserine exposure and/or increased TF activity on acrolein-treated cells. Despite elevated levels of thrombin generation, plasma APC levels were not elevated. In vivo, treatment of mice with cyclophosphamide and acrolein resulted in elevations of plasma TAT complex levels, whereas APC levels remained low. This is the first study to examine thrombin generation and the APC pathway in chemotherapy-treated mice. Cyclophosphamide and acrolein appear to upregulate procoagulant pathways, while impairing endogenous anticoagulant pathways. This may explain, in part, the increased risk of thrombosis observed in cancer patients receiving cyclophosphamide-containing chemotherapy.

Determination of three anti-tuberculosis medicines in focus of patients with tuberculosis of the wrist and its clinical significance

Objective To study the distribution of rifampicin,isoniazid in tissues of patients with tuberculosis wrist for the sake of providing siven guide toward operation and postoperative chemotherapy.Methods 32 patients with tuberculosis wrist,according to radiographic data,were divided into Center group(group Ⅰ)and Borderline groups(group Ⅱ).All patients received chemotherapy regimen of 3SHR(T)Z/6HR(T).After treatment for4 weeks,the patients'specimen of serum,and tuberculosis tissues(group Ⅰ)including sclerotic bone wall,sub-normal bone and tuberculosis tissues(group Ⅱ)including dissolved bone wall,sub-normal bone were obtained during operation at 1,2 hours respectively after oral medication.Then pretreatment and mensuration using HPLC method were carried out after specimen's removal.Results Concentrations of isoniazid and rifapentine in(group Ⅰ)and(group Ⅱ)sub-normal bone and dissolved bone were abeve the minimal bactericidal concentration values.Concentration of 2 drugs in(group Ⅰ)sclerotic bone wall were much lower than that in sub-normal bone and dissolved bone wall.Conclusion The concentration of 2 drugs in patients sclerotic bone wall of wrist were too lower to eliminate the mycobacterium tuberculosis,while an effective concentration for anti-tuberculosis chemotherapy should be find in sub-normal bone and dissolved bone of wrist.Thus,the sclerotic bone of wrist plays an important role in obstructing the drags penetration into tuberculosis. Key words: Tuberculosis,osteoartieular/DT; Wrist joint; Antitubercular agents/AD/PK

Angiogenesis-Related Gene Expression Profile with Independent Prognostic Value in Advanced Ovarian Carcinoma

BackgroundOvarian carcinoma is the most important cause of gynecological cancer-related mortality in Western societies. Despite the improved median overall survival in patients receiving chemotherapy regimens such as paclitaxel and carboplatin combination, relapse still occurs in most advanced diseased patients. Increased angiogenesis is associated with rapid recurrence and decreased survival in ovarian cancer. This study was planned to identify an angiogenesis-related gene expression profile with prognostic value in advanced ovarian carcinoma patients.Methodology/Principal FindingsRNAs were collected from formalin-fixed paraffin-embedded samples of 61 patients with III/IV FIGO stage ovarian cancer who underwent surgical cytoreduction and received a carboplatin plus paclitaxel regimen. Expression levels of 82 angiogenesis related genes were measured by quantitative real-time polymerase chain reaction using TaqMan low-density arrays. A 34-gene-profile which was able to predict the overall survival of ovarian carcinoma patients was identified. After a leave-one-out cross validation, the profile distinguished two groups of patients with different outcomes. Median overall survival and progression-free survival for the high risk group was 28.3 and 15.0 months, respectively, and was not reached by patients in the low risk group at the end of follow-up. Moreover, the profile maintained an independent prognostic value in the multivariate analysis. The hazard ratio for death was 2.3 (95% CI, 1.5 to 3.2; p<0.001).Conclusions/SignificanceIt is possible to generate a prognostic model for advanced ovarian carcinoma based on angiogenesis-related genes using formalin-fixed paraffin-embedded samples. The present results are consistent with the increasing weight of angiogenesis genes in the prognosis of ovarian carcinoma.

Prophylaxis of chemotherapy-induced neutropenia: Patterns of care in U.S. community oncology practices

9123 Background: Adherence to neutropenia guidelines may improve patient outcomes and decrease costs associated with febrile neutropenia (FN). This analysis presents baseline data on patterns of colony-stimulating factor (CSF) use among community-based oncology practices prior to an educational intervention targeted to health care providers to improve adherence to CSF guidelines from the National Oncology Alliance (NOA). Methods: Medical records were identified from 47 participating sites. Abstractors collected data from a sequential sample of adult cancer patients receiving chemotherapy during the year prior to site randomization to an educational intervention (June and August 2006). A complex algorithm was developed to identify patients for whom the NOA guidelines recommend primary prophylaxis with a CSF including (1) patients receiving a chemotherapy regimen with a &gt;20% expected risk of FN and (2) patients receiving chemotherapy with a 10–20% risk of FN and who have one of the following risk factors present: diminished performance status or non-Hodgkin's lymphoma with low serum albumin or high serum LDH or spread to bone marrow. Results: 2594 patients were evaluated for this analysis. Most were female (66%) and the mean age was 61.7 years (± 13.1). During this period (2005–06), 423 (16%) patients received chemotherapy regimens with an FN risk &gt;20% and 143 (6%) received chemotherapy regimens with an FN risk of 10–20% and had a risk factor. Of patients receiving chemotherapy with a &gt;20% risk of FN, 176 (42%) received CSF primary prophylaxis. Of patients receiving chemotherapy with a 10–20% risk FN with a risk factor present, 40 (28%) received CSF primary prophylaxis. Conclusions: Many patients for whom guidelines recommend treatment did not receive CSF primary prophylaxis. After the year-long educational intervention, we will re-evaluate CSF patterns of care and assess whether adherence to guidelines improved patient outcomes. No significant financial relationships to disclose.

Study on unrelated donor allogeneic bone marrow transplantation with Bu-CY2 conditioning regimen for myelodysplastic syndrome

To evaluate the efficacy and safety of Bu-CY(2) conditioning regimen on allogeneic bone marrow transplantation (BMT) with unrelated donor for myelodysplastic syndrome. Six patients received chemotherapy regimen of busulfan (Bu) and cyclophosphamide (CY) before allogeneic BMT (Bu 4 mg . kg(-1) . d(-1), -7 d - -4 d, CY 60 mg . kg(-1) . d(-1), -3 d - -2 d). Mycophenolate mofetil combined with cyclosporin A and methotrexate was used for prevention of acute graft-versus-host disease after transplantation. Lipo prostaglandin E(1)was used in prophylactic regimen for hepatic veno-occlusive disease. Neutrophil count began to be higher than 0.5 x 10(9)/Lat the 18th day after BMT. Platelet count began to be higher than 20 x 10(9)/Lat the 21st day after BMT. Disease-free survival in the six patients was 27 months. Bu-CY(2) conditioning regimen on allogeneic bone marrow transplantation with unrelated donor is an effective therapy for patients with myelodysplastic syndrome.

Microarray Analysis of Differentially Expressed Genes in Response to Retrovirally Mediated Overexpression of MDR1.

An important strategy for improving cancer therapy is the protection of healthy cells against therapy-induced damage. In this context gene therapy can complement radio- and chemotherapy in the treatment of tumours. Retroviral overexpression of P-glycoprotein (P-gp), the product of the MDR1 (multidrug resistance 1) gene, can deliver such a protective effect. P-gp possesses two relevant functions: its detoxifying effect acts as an efflux pump and could be important in high-dose chemotherapy, the anti-apoptotic effect of overexpressed P-gp could protect normal cells in tumour radio- or chemotherapy. The protection of haematopoietic stem cells in lymphoma, myeloma or solid tumor therapy is a promising candidate for this approach. However, little is known which other gene expressions might be influenced by MDR1-overexpression. Therefore we analyzed differentially expressed genes in the human lymphoblastoid cell line TK6 transduced with onco-retrovirus SF91m3 encoding MDR1 using the GeneChip Human Genome U133 Plus2.0 (Affymetrix). 61 annotated genes showed a significant change in expression (p<10−4) in MDR1 overexpressing compared to control transduced (overexpression the neomycin resistance gene) and untransduced cells. We found that genes coding for detoxifying and exocytotis proteins (e.g. ABCB4, ALDH1A, unc13) were up-regulated. Furthermore several proapoptotic genes were down-regulated (e.g. Casp1, Casp4) with concomitant increased expression of antiapoptotic genes (e.g. Akt3). The differential expressions for several genes were verified with real-time PCR. The results confirmed the dependence of these gene regulations on MDR1 overexpression. The influence of MDR1/P-gp overexpression on apoptotic signalling and cell survival was further corroborated by reduced apoptosis rates in response to irradiation in SF91m3 transduced cells compared to the control cell lines. Our genomics results support the findings from other studies that overexpression of MDR1 confers protection against apoptotic stimuli. The multidrug resistance phenotype does not seem to be only due to high P-gp expression but also to other metabolic proteins. Our results could have important implications for MDR1-gene therapy in patients receiving chemotherapy regimens in combination with radiotherapy.

ABVD with Pegfilgrastim (Neulasta) Support in Newly Diagnosed Hodgkin Lymphoma: Long-Term Safety and Efficacy Results of a Phase-II Study.

The safety and efficacy of pegfilgrastim (Neulasta) has been established in association with chemotherapeutic regimens that are repeated every 3 weeks. However, the long-term safety of pegfilgrastim in patients receiving chemotherapy regimens every 2 weeks remains under investigation. Of concern is the possibility of stem cell damage because of the long half-life that may overlap with subsequent courses of chemotherapy. ABVD chemotherapy is widely used for the treatment of patients with Hodgkin lymphoma (HL). Up to 65% of patients receiving ABVD will require growth factor support to maintain dose intensity, prevent neutropenic fever, and to prevent delays in chemotherapy administration. In this study, we used primary prophylaxis of 6 mg pegfilgrastim in first and subsequent cycles of ABVD. Patients were eligible if they were older than 16 years and had previously untreated HL patients who are scheduled to receive standard ABVD chemotherapy, adequate bone marrow reserve (ANC > 1,000/uL, Platelet > 100,000/uL, left ventricular ejection fraction > 50%, serum creatinine < 2 mg/dl, serum bilirubin < 2 mg/dl. They were excluded if they had HIV infection, were pregnant women and women or child bearing age who are not practicing adequate contraception, had prior chemotherapy, severe pulmonary disease including COPD and asthma, or history of prior sensitivity to E. coli derived products. All patients received one fixed dose of 6 mg pegfilgrastim approximately 24 hours after ABVD therapy. CBC was performed on a weekly basis, until completion of therapy, and then was monitored every 3–4 months thereafter. Twenty-five patients are enrolled, all of whom are evaluable for efficacy and toxicity. Median age is 26 (range; 19 – 81 years). Men = 14, women = 11. Twenty three pts completed at least 3 full cycles (6 doses of ABVD), and thirteen Pts completed 6 cycles. A total of 225 doses of ABVD are administered. Day 14 ANC count below 1,000/uL occurred in only 5 doses of ABVD (2%). Non-neutropenic infection developed with 7 doses (3%) requiring delay in the subsequent dose of ABVD beyond day 14. Long-term safety is available on 11 pts who had a follow-up ANC counts beyond one year after completion of ABVD treatment. The median ANC after at least one year of follow up was 2,790/uL (range 1,350 to 7,060/uL). Five pts had a follow up beyond 18 months after completion of ABVD therapy, and their median ANC was 2,300/uL (range: 1,570 to 3,360/uL). Furthermore, PK data from 5 unselected patients were performed on day 14 following the first cycle of ABVD. In all 5 patients, serum pegfilgrastim levels were below clinically significant levels. Our data demonstrate the efficacy of single dose per cycle of pegfilgrastim in maintaining ABVD dose intensity, keeping therapy on schedule, and preventing neutropenic fever. Furthermore, our preliminary long-term follow up data demonstrate the safety of pegfilgrastim administration in conjunction with standard dose ABVD chemotherapy given every 2 weeks.

326. Gene Therapeutic Overexpression of MDR1 Affects Transcriptional Regulations of Proteins Involved in Apoptosis and Detoxification

An important strategy for improving cancer therapy is the protection of healthy cells against therapy-induced damages. In this context gene therapy can complement radio- and chemotherapy in the treatment of tumours. Retroviral overexpression of P-glycoprotein (P-gp), the product of the MDR1 (multidrug resistance 1) gene, can deliver such a protective effect. P-gp possesses two relevant functions: its detoxifying effect acts as an efflux pump and could be important in high-dose chemotherapy; the anti-apoptotic effect of overexpressed P-gp could protect normal cells in tumour radio- or chemotherapy. The protection of haematopoietic stem cells in lymphoma, myeloma or solid tumor therapy is a promising candidate for this kind of MDR1 gene therapy. However, little is known which other gene expressions might be influenced by MDR1-overexpression. Therefore we analyzed differentially expressed genes in the lymphoblastoid cell line TK6 onco-retrovirally transduced with MDR1 using the GeneChip Human Genome U133 Plus2.0 (Affymetrix). 204 annotated genes of the >54000 probe sets per microarray showed a significant change in expression (P<10|[minus]|3) in MDR1 overexpressing compared to untransduced cells. We found that genes coding for detoxifying and exocytotis proteins (e.g. ALDH1A, unc13) were up-regulated. Furthermore several proapoptotic genes were down-regulated (e.g. Casp1, Casp4) with concomitant increased expression of antiapoptotic genes (e.g. Akt3). The differential expressions for seven selected genes were verified with real-time PCR comparing cDNA from MDR1 transduced versus untransduced and versus Neomycin resistance gene or hrGFP (humanized renilla green fluorescent protein) transduced TK6 cells as controls. The results confirmed the dependence of these gene regulations on MDR1 overexpression. Thus we could demonstrate that MDR1 overexpression influences the transcriptome of TK6 cells. Our genomics results support the findings from other studies that overexpression of MDR1 confers protection against apoptotic stimuli. The multidrug resistance phenotype does not seem to be only due to high P-gp expression but also to other metabolic proteins. These results could have important implications for MDR1-gene therapy in patients receiving chemotherapy regimens in combination with radiotherapy.

Long-Term Safety and Efficacy of Single Administration of a Fixed Dose Pegfilgrastim (Neulasta) in Inducing Neutrophil Count Recovery after ABVD Chemotherapy in Patients with Hodgkin Lymphoma.

Pegfilgrastim (Neulasta) is a pegylated form of G-CSF that has a long half-life allowing for a single administration per chemotherapy cycle. Although the safety and efficacy of pegfilgrastim has been established in association with chemotherapeutic regimens that are repeated every 3 weeks, its safety in patients receiving chemotherapy regimens every 2 weeks is currently under investigation. Of concern is the possibility of stem cell damage because of the long half life that may overlap with subsequent courses of chemotherapy. ABVD chemotherapy is widely used for the treatment of patients with Hodgkin disease. Up to 65% of patients receiving ABVD will require growth factor support to 1) maintain dose intensity 2) to prevent neutropenic fever and 3) to prevent delays in chemotherapy administration. In this study, we used a single dose per cycle of 6 mg pegfilgrastim in first and subsequent cycles of ABVD. Patients were eligible if they were older than 16 years and had previously untreated Hodgkin's disease patients who are scheduled to receive standard ABVD chemotherapy, adequate bone marrow reserve (ANC > 1,000/uL, Platelet > 100,000/uL, left ventricular ejection fraction > 50%, serum creatinine < 2 mg/dl, serum bilirubin < 2 mg/dl. They were excluded if they had HIV infection, were pregnant women and women or child bearing age who are not practicing adequate contraception, had prior chemotherapy, severe pulmonary disease including COPD and asthma, or history of prior sensitivity to E.coli derived products. All patients received one fixed dose of 6 mg pegfilgrastim 24 hours after ABVD therapy. CBC was performed on a weekly basis, until completion of therapy, and then was monitored every 3–4 months thereafter. Twenty-five patients are enrolled, all of whom are evaluable for efficacy and toxicity. Median age is 26 (range; 19 – 81 years). Men = 14, women = 11. Twenty three pts completed at least 3 full cycles (6 doses of ABVD), and thirteen Pts completed 6 cycles. A total of 225 doses of ABVD are administered. Day 14 ANC count below 1,000/uL occurred in only 5 doses of ABVD (2%). Non-neutropenic infection developed with 7 doses (3%) requiring delay in the subsequent dose of ABVD beyond day 14. Long-term safety is available on 11 pts who had a follow-up ANC counts beyond one year after completion of ABVD treatment. The median ANC after at least one year of follow up was 2,790/uL (range 1,350 to 7,060/uL). Five pts had a follow up beyond 18 months, and their median ANC was 2,300/uL (range: 1,570 to 3,360/uL). Furthermore, PK data from 5 unselected patients were performed on day 14 following the first cycle of ABVD. In all 5 patients, serum pegfilgrastim levels were below clinically significant levels. Our data demonstrate the efficacy of single dose per cycle of pegfilgrastim in maintaining ABVD dose intensity, keeping therapy on schedule, and preventing neutropenic fever. Furthermore, our preliminary long-term follow up data demonstrate the safety of pegfilgrastim administration in conjunction with standard dose chemotherapy given every 2 weeks.

Balancing the benefits and costs of colony-stimulating factors: a current perspective

Neutropenia is the most common dose-limiting toxicity associated with cancer chemotherapy. Neutropenic complications, including febrile neutropenia, occur in a substantial proportion of patients with chemotherapy-induced neutropenia. Although neutropenia and its complications can be reduced with colony-stimulating factors (CSFs), it is not considered cost-effective to administer them prophylactically to all patients. The current American Society of Clinical Oncology guidelines recommend primary prophylaxis with the CSFs in patients receiving chemotherapy regimens that produce febrile neutropenia in 40% or more of those treated. This recommendation was supported by an early economic analysis based on a decision model incorporating hospital cost data to determine the risk threshold for the cost-saving use of the CSFs. Updating this model to include current estimates of hospitalization costs, indirect costs such as productivity losses, and out-of-pocket patient expenses reduced the risk threshold for cost savings with CSF to 18%. Recent efforts have focused on identifying individual patient characteristics that might be used to target prophylactic CSF in patients who are at greatest risk. Should such factors be identified and validated, assessing each patient’s individual risk for neutropenic complications may prove to be a better strategy for the cost-effective use of the CSFs than the risk threshold approach. Preliminary results suggest that the targeted application of CSF support based on a risk model may improve the associated cost savings.