Primary Colony-stimulating Factor Prophylaxis Research Articles

Management of Germ Cell Tumors During the Outbreak of the Novel Coronavirus Disease-19 Pandemic: A Survey of International Expertise Centers.

The coronavirus disease 2019 (COVID-19) pandemic has become a public health emergency affecting frail populations, including patients with cancer. This poses the question of whether cancer treatments can be postponed or modified without compromising their efficacy, especially for highly curable cancers such as germ cell tumors (GCTs). To depict the state-of-the-art management of GCTs during the COVID-19 pandemic, a survey including 26 questions was circulated by e-mail among the physicians belonging to three cooperative groups: (a) Italian Germ Cell Cancer Group; (b) European Reference Network-Rare Adult Solid Cancers, Domain G3 (rare male genitourinary cancers); and (c) Genitourinary Medical Oncologists of Canada. Percentages of agreement between Italian respondents (I) versus Canadian respondents (C), I versus European respondents (E), and E versus C were compared by using Fisher's exact tests for dichotomous answers and chi square test for trends for the questions with three or more options. Fifty-three GCT experts responded to the survey: 20 Italian, 6 in other European countries, and 27 from Canada. Telemedicine was broadly used; there was high consensus to interrupt chemotherapy in COVID-19-positive patients (I = 75%, C = 55%, and E = 83.3%) and for use of granulocyte colony-stimulating factor primary prophylaxis for neutropenia (I = 65%, C = 62.9%, and E = 50%). The main differences emerged regarding the management of stage I and stage IIA disease, likely because of cultural and geographical differences. Our study highlights the common efforts of GCT experts in Europe and Canada to maintain high standards of treatment for patients with GCT with few changes in their management during the COVID-19 pandemic. Despite the chaos, disruptions, and fears fomented by the COVID-19 illness, oncology care teams in Italy, other European countries, and Canada are delivering the enormous promise of curative management strategies for patients with testicular cancer and other germ cell tumors. At the same time, these teams are applying safe and innovative solutions and sharing best practices to minimize frequency and intensity of patient contacts with thinly stretched health care capacity.

Use of colony-stimulating factor primary prophylaxis and incidence of febrile neutropenia from 2010 to 2016: a longitudinal assessment

Background: Guidelines recommend primary prophylactic use of colony-stimulating factor (PP-CSF) when risk of febrile neutropenia (FN) – based on chemotherapy and patient risk factors – is high. Whether and how PP-CSF use may have changed over time (e.g. due to guideline revisions, increasing use of myelosuppressive regimens, controversy regarding inappropriate CSF use), and whether there has been a concomitant change in the incidence of FN, is unknown.Methods: A retrospective cohort design and data from two US healthcare claims repositories were employed. The study population included patients who had non-metastatic cancer of the breast, colon/rectum, lung or ovaries, or non-Hodgkin’s lymphoma (NHL), and who received myelosuppressive chemotherapy regimens with an intermediate/high risk for FN. For each patient, the first cycle of the first course was characterized in terms of PP-CSF use and FN episodes. Crude incidence proportions for PP-CSF and FN during the first cycle were estimated by calendar quarter (2010–2016); multivariable logistic regression models were used to estimate quarter-specific adjusted mean probabilities of FN by PP-CSF use.Results: The study population totaled 142,730 patients with breast cancer (61%), colorectal cancer (14%), NHL (11%), ovarian cancer (10%) or lung cancer (5%). PP-CSF use increased from 52% in 1Q2010 to 58% in 4Q2016; pegfilgrastim was the most commonly used agent (>96% across quarters). PP-CSF administration on the same day as chemotherapy ranged from 8 to 11% until 1Q2015, and increased to 64% by 4Q2016. Adjusted incidence proportions for FN in the first chemotherapy cycle ranged from 2.7% (95% CI: 2.3–3.0) to 3.7% (95% CI: 3.1–4.3) among those who did not receive PP-CSF, and was 2.6% (95% CI: 2.5–2.7) across quarters among those who received PP-CSF.Conclusions: Although the use of PP-CSF is commonplace in current US clinical practice, underutilization in cancer patients receiving chemotherapy regimens with an intermediate/high risk for FN may still be an issue. Use of same-day PP-CSF increased markedly from the end of 2015, although this finding reflects (at least in part) increased uptake of pegfilgrastim delivered via an on-body injector as well as the recent change in clinical practice guidelines. Overall, patients receiving PP-CSF appear to have a lower risk of FN during the first cycle of chemotherapy.

Association of risk of febrile neutropenia (FN) with docetaxel in prostate cancer (PC) patients: A meta-analysis of published phase II-III trials.

e21683 Background: Reported rates of FN with docetaxel (DTX) in PC patients are variable. This creates uncertainty regard the use of granulocyte colony-stimulating factor primary prophylaxis (G-CSF) in this setting. We conducted a meta-analysis of randomized clinical trials to determine the relative risk (RR) of FN in patients receiving DTX. Methods: To perform this analysis we systematically searched in PUBMED and MEDLINE database the following terms: “DTX”, “randomized clinical trial” and “prostate cancer” only for articles published between January 1996 and August 2016. Phase II-III clinical studies comparing DTX to non-DTX control arms (best supportive care [BSC] including non-cytotoxic therapy or mitoxantrone) for PC were included. The meta-analyses were performed by computing RRs with 95% confidence intervals (CI) using fixed-effects model with the Mantel-Haenszel method. Results: Seven studies (N = 5088 patients) were included. The global incidence of FN in patients treated with DTX was 10.7%. The RR of FN was higher in patients receiving DTX compared to patients did not receive DTX (RR 16.8 [95% CI 10.7; 26.4] p < 0.0001). 6.6% of patients with metastatic castration resistant prostate cancer (CRPC) treated with DTX developed FN, the RR of FN with DTX compared to mitoxantrone was 28.6 (95% CI 5.6; 145.1). 12.4% of patients with hormone-sensitive prostate cancer (HSPC) treated with DTX developed FN, the RR of FN was 15.3 (95% CI 9.6; 24.6) compared to BSC. There was no statistically significant differences in the rate of FN according to the hormone sensitivity (HSPC vs CRPC) (p = 0.7). In most studies the use of G-CSF was at the discretion of the investigator. Conclusions: This meta-analysis shows that DTX is associated with a significant increase in the relative risk of FN in patients with PC. The effectiveness of primary prophylactic G-CSF in this setting has not been fully established. The incidence reported here does not meet the threshold recommended by ESMO and ASCO guidelines for the use of prophylactic G-CSF. Special attention should be given to high risk groups for FN, including elderly patients and those with bone marrow involvement or previous radiotherapy/chemotherapy.

P2.03a-008 Relative Dose Intensity of First-Line Chemotherapy and Overall Survival in Patients With Advanced Non–Small-Cell Lung Cancer (NSCLC)

For patients with advanced NSCLC, chemotherapy dose reductions/delays are commonly used to manage toxicities. However, there is limited information on the relationship between relative dose intensity (RDI) and survival in metastatic NSCLC. Objective: Describe the relationship between RDI and survival in patients with NSCLC in a US community oncology practice setting. This was a retrospective study using the McKesson Specialty Health/US Oncology iKnowMedSM electronic health record database. Inclusion criteria: Patients with advanced (stage III/IV) NSCLC who initiated first-line, intravenous, myelosuppressive chemotherapy between January 2007 and December 2010. Endpoints: Mean RDI (a composite measure including both dose delays and dose reductions), RDI <85%, and incidences of dose delays ≥7 days and dose reductions ≥15% in any chemotherapy cycle. Dosing analysis covered a period up to 6 months after chemotherapy initiation. Uni-variable and multivariable analyzes for survival were conducted using Cox proportional hazard regression. Overall, 3866 patients with NSCLC were included; the most common chemotherapy regimens included carboplatin/taxol (n=1733), pemetrexed/carboplatin (n=789), and bevacizumab/carboplatin/taxol (n=734). 709 (18.3%) received colony-stimulating factor primary prophylaxis. The mean (SD) RDI was 83.9% (28.5%), the incidence of RDI <85% was 40.4%, and the incidence of dose delays ≥7 days and dose reductions ≥15% were 32.4% and 50.1%, respectively. Uni-variable analysis suggested that dose delay ≥7 days was associated with a 22.4% reduction in the risk of death (P<0.0001). Multivariable analysis suggested that RDI and dose delay were significant predictors of survival after controlling for covariates. RDI <85% and dose delay ≥7 days were associated with a 17.6% increase and a 29.0% reduction in risk of death, respectively (Table). Reduced RDI and chemotherapy dose delays were common in advanced NSCLC and significantly associated with survival in a multivariable analysis. Understanding the complex effect of dose intensity on outcomes will be important for managing toxicities and improving survival.TableMultivariable Cox Regression Analysis for Overall Survival for Patients with Lung CancerVariableHR (95%CI)P ValueRDI <85% (reference: ≥85%)1.176 (1.047–1.320)0.0062Dose delay ≥7 days (reference: <7 days)0.710 (0.630–0.800)<0.0001ECOG performance status (reference: status of 0)11.316 (1.192–1.453)<0.000121.654 (1.350–2.027)<0.0001Hemoglobin <12 g/dL (reference: ≥12 g/dL)1.098 (0.993–1.213)0.0686Tumor subgroups (reference: squamous)Adenocarcinoma0.783 (0.698–0.877)<0.0001Other0.932 (0.725–1.199)0.5855ECOG=Eastern Cooperative Oncology Group; HR=hazard ratio; RDI=relative dose intensity. Open table in a new tab

The risk of febrile neutropenia and need for G-CSF primary prophylaxis with the docetaxel and cyclophosphamide regimen in early-stage breast cancer patients: a meta-analysis.

The febrile neutropenia (FN) rates reported with the docetaxel 75 mg/m(2) plus cyclophosphamide 600 mg/m(2) (TC) regimen given every 3 weeks vary from 4 to 69 % in early-stage breast cancer (ESBC) patients. This creates uncertainty as to whether patients receiving the TC regimen should also receive granulocyte colony-stimulating factor primary prophylaxis (G-CSFpp), which is recommended when chemotherapy regimens have ≥20 % FN rate. We conducted a meta-analysis of published studies to determine FN rate with the TC regimen, its dependence on patients' age, and the efficacy of G-CSFpp in reducing it in ESBC patients. We systematically searched the literature via PUBMED using the following terms: 'docetaxel', 'cyclophosphamide', 'febrile neutropenia', and 'breast cancer'. Inclusion criteria were full text peer-reviewed clinical studies in English reporting FN rates with TC regimen in relationship to G-CSFpp. Comprehensive meta-analysis software was used for all statistical analyses. Eight studies (N = 1542 patients) were included in our meta-analysis. The pooled mean FN rate was 23.2 % (95 % confidence interval (CI) 6.9-55.2 %; Q = 218.17, I (2) = 97.7). The FN risk in <65 years old patients was lower by 67.7 % compared to that in patients ≥65 years old (pooled odds ratio (OR) 0.323; 95 % CI 0.127-0.820; P = 0.017). The FN risk was reduced by 92.3 % with G-CSFpp (pooled OR 0.077; 95 % CI 0.013-0.460; P = 0.005). Our meta-analysis demonstrated that TC regimen was associated with ≥20 % FN risk, which was significantly higher in patients ≥65 years old and improved with G-CSFpp. G-CSFpp should be considered for all ESBC patients receiving TC regimen, especially those ≥65 years old.

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

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

Safety and tolerability of docetaxel, cyclophosphamide, and trastuzumab compared to standard trastuzumab-based chemotherapy regimens for early-stage human epidermal growth factor receptor 2-positive breast cancer.

PurposeWe evaluated the tolerability and cardiac safety of docetaxel, cyclophosphamide, and trastuzumab (TCyH) for the treatment of early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer and compared to the standard trastuzumab-based chemotherapy regimens doxorubicin with cyclophosphamide followed by paclitaxel and trastuzumab (AC-TH) and docetaxel, carboplatin, and trastuzumab (TCaH).MethodsWe retrospectively reviewed early-stage, resectable, HER2-positive breast cancer patients treated with trastuzumab-based chemotherapy at a single comprehensive cancer center between 2004 and 2011. Patient characteristics, comorbidities, relative dose intensity (RDI) of each regimen, tolerability, and cardiac toxicity were evaluated.ResultsOne hundred seventy-seven patients were included in the study (AC-TH, n=114; TCaH, n=39; TCyH, n=24). TCyH was solely administered in the adjuvant setting, whereas two-thirds of the AC-TH and TCaH groups were administered postoperatively. Patients treated with TCyH tended to have a more significant underlying cardiac history, higher Charlson comorbidity index, and were of an earlier stage. All patients treated with TCyH received granulocyte colony stimulating factor primary prophylaxis. No febrile neutropenia or grade ≥3 hematologic toxicity was observed in the TCyH group as compared to the AC-TH and TCaH groups. There were no significant differences in the rates of early termination, hospitalization, dose reduction, or RDI between the regimens. The symptomatic congestive heart failure rate between AC-TH, TCaH, and TCyH groups was not significantly different (4.4% vs. 2.6% vs. 8.3%, respectively, p=0.57). There was also no significant difference in the rate of early trastuzumab termination between patients treated with each regimen.ConclusionTCyH is well tolerated and should be investigated as an alternative adjuvant chemotherapy option for patients who are not candidates for standard trastuzumab-containing regimens. Larger clinical trials are necessary to support the wider use of TCyH as an adjuvant regimen.

Clinical practice in febrile neutropenia risk assessment and granulocyte colony-stimulating factor primary prophylaxis of febrile neutropenia in Poland.

Aim of the studyThe first aim was to investigate the knowledge and awareness of oncologists concerning febrile neutropenia (FN) risk assessment and indications for granulocyte colony-stimulating factor (G-CSF) primary prophylaxis (PP), based on current therapeutic guidelines (PTOK and EORTC). The second aim was to educate the oncologists on best practices for risk assessment and neutropenia management.Material and methodsThe project participants included 169 oncologists from 7 regions working in large specialist oncological centres, university hospitals, regional and city hospitals, specialist outpatient clinics, and oncological wards in small local hospitals. The participants completed a questionnaire based on seven prepared clinical cases of patients with different tumour types and patient characteristics, receiving chemotherapy (CT), and with different levels of FN risk. Participants answered questions related to FN risk assessment and G-CSF use. After completing the questionnaire, the participants proceeded to an educational module in which they were provided with an analysis of correct diagnostic and therapeutic procedures according to the PTOK and EORTC guidelines.Results and ConclusionsFebrile neutropenia risk assessment was found to be a routine procedure performed for over 90% of the clinical cases by the participant oncologists. However, the FN risk assessment of clinical cases was correct and consistent with therapeutic guidelines in only 65% of responses. Indications for G-CSF PP were properly identified in 76% of responses and it appeared that indications for G-CSF PP were more likely to be correctly identified in patients receiving high-risk or low-risk regimens than in those receiving intermediate-risk regimens, where the decision to give G-CSF PP is based on additional assessment of patient risk factors. The vast majority of participants who correctly identified the need for PP administered G-CSF in accordance with the dose and schedule recommended by PTOK and EORTC.

Abstract P3-13-09: Relative dose intensity of taxane-based chemotherapy in patients with stage IV breast cancer

Abstract Background: Maintaining high relative dose intensity (RDI) has been associated with improved disease-free survival, progression-free survival, and overall survival of patients with breast cancer treated in the adjuvant setting. Neutropenia and related complications, such as febrile neutropenia, are common side effects of myelosuppressive chemotherapy that can lead to dose delays, dose reductions, and reduced RDI. Primary prophylaxis with colony-stimulating factors (CSFs) can reduce the duration and severity of neutropenia and the incidence of febrile neutropenia, thereby supporting high RDI. For patients with stage IV breast cancer, dose delays and dose reductions are frequently used to manage toxicity associated with myelosuppressive chemotherapy. However, the prevalence and impact of reduced RDI in the metastatic disease setting is poorly understood. Objective: To estimate mean chemotherapy RDI and incidences of dose delays, dose reductions, RDI &amp;lt;85%, and primary CSF prophylaxis among women with stage IV breast cancer receiving first-line chemotherapy. Methods: Using the McKesson Specialty Health/US Oncology iKnowMed™ electronic health record (HER) database, we retrospectively identified adult women with stage IV breast cancer who initiated first-line, intravenous, myelosuppressive chemotherapy from January 2007 to December 2010 in community oncology practices in the US. Patients were assigned to chemotherapy cohorts based on myelosuppressive agents received in cycle 1 and planned regimen information in the database. Standard chemotherapy regimens were defined based on NCCN breast cancer guidelines and clinical studies. Mean RDI and incidences of dose delays ≥7 days, dose reductions ≥15%, and RDI &amp;lt;85% in any cycle during the course of chemotherapy were evaluated relative to the standard chemotherapy regimen. Primary CSF prophylaxis was defined as first receipt of CSF during the first 5 days of chemotherapy cycle 1. Patients were followed for up to 6 months after chemotherapy initiation. Results: This study included 1471 patients with stage IV breast cancer who received myelotoxic chemotherapy. The most common chemotherapy regimens in the metastatic setting were taxane-based, and endpoints for the three most common chemotherapy regimens (n = 307) are shown in the Table. Paclitaxel/ BevacizumabaAlbumin-bound PaclitaxelbPaclitaxelcN1767556Age, mean (SD) years58.2 (11.9)63.6 (12.4)61.8 (13.8)RDI, mean (SE)89.0% (1.9)89.1% (3.1)89.0% (3.2)RDI &amp;lt;85%37.5%41.3%26.8%Dose delays ≥7 days36.9%22.7%32.1%Dose reductions ≥15%40.9%61.3%8.9%CSF primary prophylaxis0%1.3%3.6%aPaclitaxel 80-90 mg/m2 on days 1, 8, and 15 and bevacizumab 10 mg/kg on days 1 and 15 (cycle length 28 days). Paclitaxel dose at cycle 1, day 1 was defined as the standard dose for this regimen; bAlbumin-bound paclitaxel 100 mg/m2 on days 1, 8, and 15 (cycle length 28 days); cPaclitaxel 80 mg/m2 (cycle length 7 days). Conclusions: Chemotherapy dose delays, dose reductions, and reduced RDI were common in patients with stage IV breast cancer. The impact of RDI on progression-free and overall survival is being evaluated and will be presented. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-13-09.

Abstract P1-15-04: The relationship of relative dose intensity and supportive care to febrile neutropenia rates in patients with early stage breast cancer receiving chemotherapy: a prospective cohort study of chemotherapy-associated toxicity

Abstract Background: Febrile neutropenia (FN) represents a major dose-limiting toxicity of cancer chemotherapy resulting in considerable morbidity, mortality, and cost. Patients have the highest risk of the initial neutropenic event in cycle 1 when most patients receive full dose chemotherapy. This study evaluates time course of neutropenic events in patients receiving chemotherapy for early-stage breast cancer (ESBC) and supportive care interventions that modify FN risk in ESBC patients treated in actual oncology practice. Methods: A prospective cohort study of adult cancer patients with solid tumors or lymphoma starting a chemotherapy regimen was conducted at 115 U.S. sites. Toxicities associated with chemotherapy were recorded in up to 4 cycles including severe neutropenia (SN), FN, and infection. Documented clinical interventions included reductions in chemotherapy relative dose intensity (RDI), the use of colony-stimulating factors (CSFs), and antibiotics. Results: A total of 1202 ESBC patients starting chemotherapy were analyzed, of which 1154, 1099, and 896 reached the midcycle of cycles 2, 3, and 4, respectively. While the majority of neutropenic and infection events occurred in cycle 1, decreasing rates of FN and infection in later cycles correlated with increasing reductions in dose intensity and increased use of CSFs and antibiotics. The overall risk of FN in all patients combined was 16.3 %. It reached 21.1% for patients who started with planned RDI≥85% and without primary CSF prophylaxis. There was no significant difference in FN rates by menopausal status or hormone receptors. Conclusions: While the risk of neutropenic complications is highest during the first cycle of chemotherapy, reductions in neutropenic events during subsequent cycles are associated with reduced chemotherapy dose intensity or increased use of supportive care measures. Nevertheless, the cumulative risk of neutropenic events remains high in ESBC patients receiving full dose chemotherapy without prophylactic measures overall and across menopausal and hormone receptor subgroups. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-04.

P5-20-03: Personalizing Supportive Care: A Clinical Prediction Model for Neutropenic Complications in Patients with Early-Stage Breast Cancer (ESBC) Receiving Intermediate Risk Chemotherapy.

Abstract Background: Neutropenic complications including severe and febrile neutropenia (FN) represent major dose-limiting toxicities of cancer chemotherapy. A general risk model for neutropenic complications across major solid tumors has been developed and validated (Lyman et al. Cancer 2011). Current guidelines recommend consideration of primary prophylaxis with a colony-stimulating factor (CSF) in patients at &amp;gt;20% risk of FN. The decision for primary CSF prophylaxis in patients on intermediate risk chemotherapy (10-20%) is based on physician assessment of individual patient risk factors for FN. This study assesses the ability of this general FN risk model to identify ESBC patients on intermediate risk chemotherapy who are at a personal high risk for developing a neutropenic complication. Methods: A prospective cohort study accrued 4458 consenting patients starting a new chemotherapy regimen at 115 randomly selected community oncology practices throughout the United States from 2002–2006. The risk of severe or febrile neutropenia (SNFN) in cycle 1 and across 4 cycles was estimated [±95% CI] utilizing logistic regression analysis and adjusting for key clinical factors including among others: age, prior chemotherapy, abnormal hepatic or renal function, low pretreatment white blood count, immunosuppressive medications, CSF prophylaxis, and planned relative dose intensity as well as major chemotherapeutic agents. The cumulative risk of FN across 4 cycles was also estimated by the product limit method of Kaplan and Meier. Results: Among 1224 patients with ESBC, 822 received intermediate risk chemotherapy based on National Comprehensive Cancer Network guidelines. Among these patients, cycle 1 SNFN occurred in 37%, at least one episode of FN over 4 cycles of chemotherapy in 17%, with 15% receiving primary CSF prophylaxis. The predicted risk of cycle 1 SNFN ranged from 1%-79%, with mean (median) risk of 33.8% (39.0%). Model performance was good with a c-statistic of 0.73 [0.69−0.76]. Based on this general FN risk model, cycle 1 SNFN occurred in 47% of predicted high risk ESBC patients [42 — 52%] compared to 13% [8-17%] of low risk patients. One or more FN events over 4 cycles occurred in 20% [17-24%] of predicted high risk versus 10% [6-14%] in low risk patients. The cumulative risk of FN by Kaplan-Meier estimation was 23% in high risk and 10% in low risk patients. Model sensitivity and specificity for FN were 83% and 33%, respectively. The majority of SNFN (76%) and FN (58%) events among high risk patients occurred in cycle 1. 50% of high risk patients who did not receive primary CSF prophylaxis went on to receive CSF during subsequent cycles. Conclusions: Based on good test performance characteristics, this clinical FN prediction model also identifies ESBC patients receiving intermediate risk chemotherapy at high personal risk for FN (FN &amp;gt;20%) over the first 4 cycles of chemotherapy. Half of predicted high risk patients without primary CSF prophylaxis will be given CSF in subsequent cycles after the occurrence of a neutropenic complication. This also confirms previous clinical trial findings that the majority of febrile neutropenic events occur in the first cycle. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P5-20-03.

Personalizing Cancer Supportive Care: Predicting Neutropenic Complications in Patients Receiving Intermediate Risk Cancer Chemotherapy

Abstract 1022 Background:Neutropenic complications represent important dose-limiting toxicities of cancer chemotherapy. We recently developed and validated a risk model for neutropenic complications in patients with solid tumors or lymphoma receiving cancer chemotherapy (Lyman et al. Cancer 2011). While practice guidelines recommend primary colony-stimulating factor (CSF) prophylaxis for patients at >20% risk of febrile neutropenia (FN), many patients receive chemotherapy regimens associated with an intermediate risk (10–20%) of FN. For these patients, the decision to give or withhold primary CSF prophylaxis is based on clinical judgment. We report here the ability of the risk model to identify patients with individual characteristics placing them at high risk for neutropenic complications among patients receiving intermediate risk chemotherapy regimens. Methods:A prospective cohort study was conducted of consenting patients initiating a new chemotherapy regimen at 115 randomly selected US oncology practices between 2002–2006. The risk of cycle 1 severe or febrile neutropenia was estimated [95% CI] utilizing logistic regression analysis adjusting for key clinical factors including: planned chemotherapy, prior chemotherapy, age, abnormal hepatic or renal function, low pretreatment white blood count, and immunosuppressive medications. The cumulative incidence of severe neutropenia and FN across 4 cycles was estimated by the product limit method of Kaplan and Meier. Results:Among 3,760 patients with cancers of breast, lung, ovary, colon, or lymphoma, 2,270 received an intermediate risk chemotherapy regimen based on NCCN guidelines. Overall, in the subpopulation receiving intermediate risk regimens, severe or febrile neutropenia occurred in cycle 1 in 21.4% while FN over 4 cycles was observed in 11%, and primary CSF prophylaxis was utilized in 16.4%. The performance of the risk model was good in this subgroup with a c-statistic of 0.82 [0.80–0.84]. Among the half of patients classified as high risk based on the model despite receiving an intermediate risk chemotherapy regimen, cycle 1 severe or febrile neutropenia occurred in 38% [35%–41%] compared to 5% [4%–6%] of patients classified as low risk based on the model receiving such regimens. Model sensitivity and specificity were 89% and 61%, respectively. The cumulative risk of FN over 4 cycles of chemotherapy was 20% in predicted high risk group versus 5% in the low risk group (Figure). The majority of severe or febrile neutropenia events (67%) and FN events (55%) were observed in cycle 1. One-half of high risk patients who did not receive primary CSF prophylaxis in cycle 1 received CSF during subsequent cycles following a neutropenic event. Conclusions:Our model for predicting neutropenic complications can identify patients at high individual risk for severe neutropenia in cycle 1 or FN in the first 4 cycles of chemotherapy when receiving intermediate risk chemotherapy. This analysis emphasizes the potential value of determining an individual patient's risk of chemotherapy complications based on a validated risk model. [Display omitted] Disclosures:Lyman:Amgen: Research Funding. Crawford:Amgen: Consultancy, Honoraria, Research Funding. Dale:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuderer:Amgen: Research Funding.

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

Neutrophil toxicity and primary prophylaxis in diffuse large B cell lymphoma treated with R-CHOP

e19548 Background: Three weekly R-CHOP therapy is regarded as standard treatment in advanced stage Diffuse Large B Cell Lymphoma (DLBCL) patients with low to intermediate-risk International prognostic index (IPI). This regimen is associated with intermediate risk (10–20%) of febrile neutropenia. Primary prophylaxis with colony-stimulating factor (CSFs) is therefore not recommended except in the presence of high risk factors as defined in the National Comprehensive Cancer Center Network guidelines for use of myeloid growth factors v.1.2008. It is however well realized that a significant number of good risk patients will still develop significant neutrophil toxicity. Methods: This observational study was conducted at Oncology department Combined Military Hospital, Rawalpindi, on fifty good risk patients of advanced stage DLBCL, treated with R-CHOP regimen without primary CSFs prophylaxis. NCI Common Toxicity Criteria version 3.0 was used for grading toxicity and significant neutrophil toxicity was defined as Grade 4 neutropenia between day 7 and 10 post therapy, febrile neutropenia and Grade 2 or more neutrophil toxicity persisting on day 1 of next cycle. Good risk patients were recruited by the following exclusion criteria: WHO Performance status scale 4, concurrent immunosuppressive drug therapy, abnormal hepatic or renal functions and inadequate hematological values. Results: 10(20%) patients, developed significant neutrophil toxicity. In this group 7(70%) had grade 4 neutropenia and 3(30%) patients developed febrile neutropenia. 8(80%) of these patients developing significant toxicity had WHO Performance scale ≥ 2. 2(20%) patients developing Grade 4 toxicity between days 7 and 10 post therapy had good performance status (0 or 1) and toxicity resolved by next cycle without getting complicated to febrile neutropenia. Conclusions: Performance status in terms of scale has not been defined in the high risk factors for developing febrile neutropenia in the NCCN guidelines on myeloid growth factors use. We observed that DLBCL patients with WHO performance status scale ≥ 2 treated with R-CHOP therapy at 3 weekly intervals are at greatest risk for developing significant neutrophil toxicity and febrile neutropenia. No significant financial relationships to disclose.

Multivariate analysis of febrile neutropenia occurrence in patients with non-Hodgkin lymphoma: data from the INC-EU Prospective Observational European Neutropenia Study.

Myelosuppression, particularly febrile neutropenia (FN), are serious dose-limiting toxicities that occur frequently during the first cycle of chemotherapy. Identifying patients most at risk of developing FN might help physicians to target prophylactic treatment with colony-stimulating factor (CSF), in order to decrease the incidence, or duration, of myelosuppression and facilitate delivery of chemotherapy as planned. We present a risk model for FN occurrence in the first cycle of chemotherapy, based on a subgroup of 240 patients with non-Hodgkin lymphoma (NHL) enroled in our European prospective observational study. Eligible patients had an International Prognostic Index of 0–3, and were scheduled to receive a new myelosuppressive chemotherapy regimen with at least four cycles. Clinically relevant factors significantly associated with cycle 1 FN were older age, increasing planned cyclophosphamide dose, a history of previous chemotherapy, a history of recent infection, and low baseline albumin (<35 g/l). Prophylactic CSF use and higher weight were associated with a significant protective effect. The model had high sensitivity (81%) and specificity (80%). Our model, together with treatment guidelines, may rationalise the clinical decision of whether to support patients with CSF primary prophylaxis based on their risk factor profile. Further validation is required.

Final Risk Prediction Model for Neutropenic Complications in Patients Receiving Cancer Chemotherapy

Introduction: Neutropenic complications including severe neutropenia (SN) and febrile neutropenia (FN) represent major dose-limiting toxicities of cancer chemotherapy. A prospective study was undertaken to develop and validate a predictive model for neutropenic events in patients receiving cancer chemotherapy. The final risk model based on mature data is presented.Methods: Between 2002 and 2006, 4458 consenting patients starting a new chemotherapy regimen at 115 randomly selected community oncology practices throughout the United States were enrolled including 3760 with cancers of breast, lung, colorectum, ovary and malignant lymphoma receiving at least one cycle of treatment. Using a 2:1 random split sample methodlogy, a risk model for first-cycle SN or FN was derived and validated based on multivariate logistic regression analysis incorporating pretreatment variable information. The cumulative risk of events over the initial 120 days of treatment was estimated by the method of Kaplan and Meier. High and low risk groups were defined on the basis of the median predicted risk and model test performance characteristics were estimated.Results: Following adjustment for cancer type, important predictive factors included: older age, prior chemotherapy, abnormal hepatic or renal function, low pretreatment white blood count, immunosuppressive medications and planned relative dose intensity >85% as well as use of several specific chemotherapeutic agents including anthracyclines, taxanes, alkylating agents, topoisomerase inhibitors, gemcitabine or vinorelbine. Lower risk of neutropenic complications were associated with primary prophylaxis with a colony-stimulating factor (CSF). Individual risk estimates based on the model ranged from 0–89% with mean and median of 19.2% and 10.1%, respectively. The model was associated with an R2 of 0.34 and demonstrated excellent discrimination with a c-statistic of 0.833 [95% CI: 0.813–0.852, P<.001]. The model predicted risk of cycle 1 SN or FN in high and low risk groups was of 34% and 4%, respectively. The cumulative risk of FN over the initial 120 days was 20% in high risk patients and 5% in low risk patients. Model performance included sensitivity and specificity of 90% and 59%, respectively, with a model diagnostic odds ratio of 12.8 [95% CI: 9.3, 17.7]. Application of the model to the validation data set was associated with similar excellent discrimination and test performance characteristics. CSF prophylaxis applied to high risk patients was associated with significantly lower risk of FN over repeated cycles of chemotherapy [HR = 0.51; 95% CI: 0.35 – 0.75; P <.0001]. Nearly two-thirds of patients classified as high risk but who did not receive primary CSF prophylaxis went on to receive secondary use during subsequent cycles.Discussion: Based on excellent test performance characteristics, the risk model identified patients with a cumulative incidence of FN of at least 20% who are candidates for targeted prophylaxis with a CSF. Further validation of this model in actual clinical practice is currently underway.

Factors related to neutropenic events in early stage breast cancer patients

634 Background: Reductions in chemotherapy relative dose intensity (RDI) in patients with early stage breast cancer (ESBC) have been shown to compromise disease-free and overall survival. A previous risk model identified factors associated with neutropenic events in patients with ESBC during the first cycle of treatment. The current analysis extends these observations to include the initial neutropenic event over multiple cycles. Methods: From 115 community oncology practices, 1,473 breast cancer patients starting a new chemotherapy regimen were enrolled in a prospective study and followed over the first 4 cycles of treatment. The primary outcome was febrile neutropenia (absolute neutrophil count (ANC) <1,000/mm3 and fever/infection) and/or severe neutropenia (ANC<500/mm3) (FN/SN). A Cox model was utilized to identify factors associated with developing FN/SN and a risk score (RS) was generated based on the model's regression coefficients. Results: Among 1,202 ESBC patients included in the analysis, 24% had stage I, 57% stage II and 18% stage III disease. Age ranged from 26 to 85 years (mean, 54 years; 16% ≥ 65 years). FN/SN was observed in 529 (44%) patients with 386 (73% of events) occurring in cycle 1. The highest proportion of neutropenic events (68%) was found with TAC (docetaxel, doxorubicin, cyclophosphamide) (p<0.0001). In multivariate analyses, planned delivery of standard chemotherapy (RDI ≥ 85%) was associated with a doubling of risk of FN/SN (hazard ratio (HR) =2.00, p<0.0001) after adjustment for treatment type (p<0.0001), glomerular filtration rate (HR=0.99, p<0.0001), baseline white blood cell count (HR=0.96, p=0.05), serum bilirubin (HR=1.76, p=0.010) and concomitant phenothiazines (HR=1.37, p=0.010). Alternatively, primary colony stimulating factor prophylaxis was associated with a reduction in FN/SN (HR=0.29, p<0.0001). Model R2 was 0.37. FN/SN rates were 10%, 32%, 57%, 78% when patients were divided into quartiles based on the calculated RS. Conclusions: The risk model presented here for FN/SN across multiple treatment cycles identified comparable risk factors to those identified previously in the model based on first cycle events. Once fully validated, the model should help identify patients at increased risk of FN or SN who may be candidates for more aggressive supportive care. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen Amgen Amgen

Neutropenia occurrence and predictors of reduced chemotherapy delivery: results from the INC-EU prospective observational European neutropenia study

Neutropenia is a life-threatening, dose-limiting toxicity of many chemotherapy regimens. The goals of this study were to assess the incidence and risk of chemotherapy-induced neutropenia, febrile neutropenia (FN) and dose limitations in breast cancer and lymphoma patients undergoing chemotherapy in Europe. Four hundred forty-four breast cancer and 305 lymphoma patients undergoing chemotherapy at 66 practices in five European countries participated in this prospective, observational study. Predictors of impaired chemotherapy delivery were investigated using a logistic regression model. In breast cancer, FN incidence was low (6%); however, grade 4 neutropenia was frequent (34%). Lymphoma patients experienced higher incidences of FN (non-Hodgkin lymphoma (NHL) 22%; Hodgkin lymphoma (HL) 15%) and grade 4 neutropenia (NHL 54%; HL 40%). For both diseases, FN and grade 4 neutropenia were associated with low relative dose intensity (RDI). Multivariate regression models indicated that first cycle FN, age > or = 65 years and Eastern Co-operative Oncology Group > 1 were associated with low RDI in breast cancer and lymphoma, while colony-stimulating factor (CSF) primary prophylaxis appeared to be protective in lymphoma only. Primary CSF prophylaxis was provided to 9% of breast cancer, 28% of NHL and 19% of HL patients. Neutropenia and low RDI remain serious problems in both breast cancer and lymphoma populations undergoing chemotherapy. Several risk factors which can trigger reduced chemotherapy delivery were identified. These results can support physicians in identifying patients most at risk of receiving impaired chemotherapy delivery who would benefit from suitable preventive measures.

Risk and Timing of Neutropenic Events in Adult Cancer Patients Receiving Chemotherapy: The Results of a Prospective Nationwide Study of Oncology Practice

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

Colony stimulating factor use and outcomes for breast, lung, and colorectal cancer patients in Washington State

6616 Background: Guidelines recommend colony stimulating factor (CSF) primary prophylaxis (PP) with chemotherapy if febrile neutropenia risk (FN) is =20%. Use of and outcomes for persons receiving CSF in clinical practice are relatively unknown. Methods: Using claims for Medicare and Medicaid enrollees linked to the Puget Sound SEER registry, breast (BCa), lung (LCa) and colorectal cancer (CRCa) patients diagnosed 2002–04 who received chemotherapy were categorized as: CSF at the start of chemotherapy (PP); other CSF; no CSF. Logistic regression was used to determine predictors of CSF PP and hospitalization for FN, controlling for cancer stage, age, sex, race, chemotherapy FN risk (from the National Comprehensive Cancer Network), radiation therapy, CSF use, health insurance, surgery =30 days of chemotherapy. Results: 364 BCa, 908 LCa, and 452 CRCa patients received chemotherapy. 43% of BCa, 30% of LCa, and 15% of CRCa patients received CSF. Only 9%, 6%, and 0.6% of patients initiated CSF as PP in the first cycle of chemotherapy. CSF use increased for all cancers, but most for BCa, (36% in 2002 to 70% in 2004); PP increased from 5% to 26%. Significant predictors (p&lt;0.05) of PP were: BCa–local vs distant stage (OR 0.2), regional vs distant (OR 0.6), chemotherapy FN risk high vs low (OR 6.7); LCa–chemotherapy FN risk high vs low (OR 8.9), intermediate vs low (OR 6.3). FN incidence was 11%, 18% and 32% for BCa, CRCa, LCa, respectively. Significant predictors of FN were: BCa–nonwhite race (OR 2.7); LCa–surgery within 30 days (OR 1.7); CRCa–regional vs. distant (OR 0.4) and chemotherapy FN risk intermediate vs. low (OR 4.2). Conclusions: CSF use has increased significantly, but often in settings where efficacy is uncertain. Cancer type, stage and chemotherapy risk of FN influenced use of primary prophylaxis. Non-chemotherapy factors also appear to influence risk for FN. No significant financial relationships to disclose.