Risk Factors For Severe Neutropenia Research Articles

Risk Factors for Eribulin-induced Severe Neutropenia in Patients With Recurrent Breast Cancer.

Eribulin is an effective chemotherapeutic agent for advanced and metastatic breast cancer. However, severe neutropenia occurs in 30-40% of patients and interferes with the recommended treatment schedule. Neutropenia is a major cause of treatment interruptions, delays, or even relative dose reductions. This study aimed to examine the risk factors for severe neutropenia after eribulin treatment. We retrospectively evaluated 263 patients with metastatic breast cancer who had received eribulin therapy. Risk factors for severe neutropenia in the first cycle were evaluated. Severe neutropenia in cycle 1 occurred in 50% of the patients. Multivariate analysis suggested six risk factors for severe neutropenia: low baseline neutrophil count and body mass index, high aspartate aminotransferase and bilirubin levels, creatinine clearance (CrCl) less than 50 ml/min, and eribulin dose of 1.4 mg/m2 Conclusion: This is one of the few studies to simultaneously examine both hepatic and renal functions in relation to severe neutropenia induced by eribulin. We have provided important information to support the close monitoring of patients with these risk factors and subsequent dosage adjustments, if necessary.

Prior treatment with oxaliplatin-containing regimens and higher total bilirubin levels are risk factors for neutropenia and febrile neutropenia in patients with gastric or esophagogastric junction cancer receiving weekly paclitaxel and ramucirumab therapy: a single center retrospective study

BackgroundWeekly paclitaxel + ramucirumab (wPTX + RAM) therapy is recommended as the standard second-line chemotherapy regimen for unresectable advanced/recurrent gastric cancer (GC) or esophagogastric junction cancer. Recent subgroup analysis of the RAINBOW trial revealed a higher frequency of severe neutropenia due to wPTX + RAM in Japanese compared to Western patients. However, no risk factors for severe neutropenia have been identified.MethodsThis retrospective observational study included patients with advanced/unresectable gastric or esophagogastric junction cancer who received wPTX + RAM after failure to respond to platinum and fluoropyrimidine doublet chemotherapy between June 2015 and April 2020. We conducted multivariable logistic regression analyses to identify the risk factors associated with grade 4 neutropenia and febrile neutropenia (FN). In addition, we investigated the relationship between the number of risk factors and overall survival (OS) and progression-free survival (PFS).ResultsAmong 66 patients who met the inclusion criteria, grade 4 neutropenia and FN occurred in 21 (31.8%) and 12 (18.2%) patients, respectively. Prior treatment with oxaliplatin-containing regimens was identified as an independent risk factor for developing grade 4 neutropenia (odds ratio (OR) 20.034, 95% confidence interval (95% CI) 3.216–124.807, P = 0.001). Total bilirubin of > 1.5 mg/dL (OR 31.316, 95% CI 2.052–477.843, P = 0.013) and prior treatment with oxaliplatin-containing regimen (OR 12.502, 95% CI 1.141–137.022, P = 0.039) were identified as independent risk factors for developing FN. Next, we classified patients with 0, 1, 2 risk factor(s) as RF-0, RF-1, and RF-2 subgroups, respectively, and compared the PFS and OS among the three subgroups. PFS was not significantly different among the three subgroups, whereas OS was significantly shorter in the RF-2 subgroup (median 1.4 month, 95% CI 0.0–5.3 month) than in the RF-0 subgroup (median 10.2 month, 95% CI 6.8–13.5 month, P < 0.01 vs RF-2) and RF-1 subgroup (median 13.3 month, 95% CI 10.9–15.7 month, P < 0.01 vs RF-2).ConclusionsCareful monitoring for grade 4 neutropenia and FN is needed for patients receiving wPTX + RAM therapy who have a history of treatment with oxaliplatin-containing regimens and higher total bilirubin levels.

Incidence of and risk factors for severe neutropenia during treatment with the modified FOLFIRINOX therapy in patients with advanced pancreatic cancer

Although FOLFIRINOX (l-Leucovorin/5-FU/Irinotecan/Oxaliplatin) is established as one of the standard therapies for patients with metastatic pancreatic cancer, the modified FOLFIRINOX (mFOLFIRINOX) is often used in clinical practice to reduce the incidence of toxicities. Febrile neutropenia (FN) and severe neutropenia during FOLFIRINOX are especially frequently observed in Japanese patients. In this study, we evaluated the incidence of FN and severe neutropenia, and explored the risk factors for severe neutropenia in patients receiving treatment with mFOLFIRINOX. The data of patients who had received mFOLFIRINOX between December 2013 and December 2014 at the National Cancer Center Hospital East were reviewed retrospectively. We graded the neutropenia severity and defined ≥ Grade 3 neutropenia as severe neutropenia. Univariate and multivariate analysis were undertaken to evaluate the associations with risk of development of severe neutropenia. A total of 122 patients were enrolled in this study. Sixty two patients (51%) and 10 patients (8%) developed severe neutropenia and FN, respectively. Multivariate analysis identified a low baseline white blood cell count (odds ratio [OR], 14.50; 95% confidence interval (CI), 3.27–111.14; p = 0.002) and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism (OR, 2.84; 95% CI, 1.18–7.17; p = 0.023) as independent risk factors for severe neutropenia. The incidences of severe neutropenia and FN in patients receiving mFOLFIRINOX in our clinical practice were comparable to previous reports. The risk factors for severe neutropenia in patients receiving mFOLFIRINOX were a low baseline white blood cell count and presence of heterozygosity for UGT1A1*28 or UGT1A1*6 polymorphism.

Risk Factors Predicting Chemotherapy-induced Severe Neutropenia and Outcome in Advanced Stage Non-small Cell Lung Cancer: Data from the Limited Resource in Thailand

Introduction: Chemotherapy-induced severe neutropenia requires dose reduction, delay in treatment, or discontinuation, and induces neutropenic complications resulting in poor outcomes and increased healthcare costs. This study aims to identify the risk factors for chemotherapy-induced severe neutropenia and outcome in advanced-stage NSCLC. Method: From July 2014-January 2019, advanced-stage NSCLC who received chemotherapy were retrospectively analyzed. Demographic and risk factors data were collected from the electronic medical record system. Univariate and multivariate logistic regression analyses were performed to identify risk factors for severe neutropenia. Survival curves were estimated using the Kaplan–Meier method. Results: Among 259 patients, 37 (14.28%) and 3 patients (1.2%) developed severe neutropenia and febrile neutropenia respectively. In multivariate analysis, restriction of protein diet (OR 9.54; 95%CI 2.44-37.24; P=0.001), concomitant use herbal medicine (OR 8.66; 95% CI 1.04-72.07; P=0.045), high BMI (OR3.1; 95% CI 1.07-8.99; P=0.04), renal disease (OR 3.9; 95% CI 1.7-8.91; P=0.001), number of cycle chemotherapy &gt; 4 (OR 3.97; 95% CI 1.11-14.18; P=0.03) were significant predictors of Chemotherapy-induced severe neutropenia. No difference in response rate, progression-free survival and overall survival among groups (RR 18.9% vs 26.7%; median PFS; 9.6 vs 8.2 months, P=0.32 and median OS 13.8 vs 16.7 months, P=0.79 in severe and non-severe neutropenia respectively).Conclusions: The present study indicates that protein-restricted diet, concomitant use of herbal medicine, BMI ≥ 25 kg/m2, renal disease, and more than 4 cycles of chemotherapy are significant risk factors for chemotherapy-induced severe neutropenia. Therefore, patients with these risk factors should be more carefully monitored.

Risk factors for severe neutropenia in pancreatic cancer patients treated with gemcitabine/nab-paclitaxel combination therapy.

AimCombination therapy with gemcitabine and nanoparticle albumin-bound paclitaxel (nab-paclitaxel), known as GnP therapy, significantly prolongs the survival of pancreatic cancer patients compared with gemcitabine monotherapy. However, it may cause severe neutropenia, requiring discontinuation of treatment. This study aimed to clarify the risk factors for Grade 3/4 neutropenia during GnP therapy.MethodsClinical data of pancreatic cancer patients who underwent GnP therapy at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research from December 2014 to December 2016 were retrospectively collected. The relationship of Grade 3/4 neutropenia onset to laboratory values and patient background factors was investigated by multivariate logistic regression analysis.ResultsClinical data of 222 patients were analyzed. Grade 3/4 neutropenia occurred in 118 patients (53.2%) in the first cycle of GnP therapy. Multivariate analysis identified low absolute neutrophil count (ANC), high total bilirubin (T-Bil), and low C-reactive protein (CRP) as risk factors for Grade 3/4 neutropenia. Age was not a risk factor. The incidence of neutropenia was 85.7% in patients with all three risk factors, but only 27.7% in patients with none of them.ConclusionLow ANC, high T-Bil, and low CRP may be risk factors for Grade 3/4 neutropenia in patients receiving GnP therapy, even if these laboratory values are within normal reference ranges. Patients with these risk factors should be carefully monitored for adverse events.

Association between severe neutropenia and progression-free survival in patients with advanced or recurrent breast cancer treated with palbociclib.

This study aimed to clarify the relationship between neutropenia and progression-free survival (PFS) under palbociclib treatment for advanced/recurrent breast cancer and the risk factors for severe neutropenia. We retrospectively identified 37 patients who received palbociclib for advanced breast cancer at Ogaki Municipal Hospital (Ogaki, Japan) between April 2018 and June 2020. Kaplan-Meier log-rank test was used to compare PFS (mild [neutrophil count 1,000-2,000/mm 3 ] versus severe [neutrophil count <500-1,000/mm³]). Multivariate analysis was performed to evaluate the relationships between baseline patient characteristics and severe neutropenia development. There were three, four, 25, and five cases with grade 1, 2, 3, and 4 neutropenia, respectively. Median PFS in patients who developed severe neutropenia (n = 30) and those who did develop mild neutropenia (n = 7) was 176 days (range: 62-894 days) and 91 days (range: 19-384 days), respectively (log-rank test, p = 0.005). Severe neutropenia was independently associated with pre-treatment neutrophil count (odds ratio: 27.700; p =0.007). Severe neutropenia is more likely to occur with a pre-treatment neutrophil count of less than 3,680 mm³. Neutropenia prolongs PFS under palbociclib treatment, suggesting management of AEs and patient education as highly important, especially to prevent drug interruption/dose reduction of palbociclib due to these AEs.

Risk factors for severe neutropenia among pancreatic cancer patients receiving nab-paclitaxel and gemcitabine combination therapy.

684 Background: Albumin-bound paclitaxel (nab-paclitaxel) and gemcitabine combination therapy (GnP therapy) significantly extends overall survival in patients with metastatic pancreatic cancer, compared to conventional gemcitabine monotherapy. However, severe neutropenia (Grade ≥ 3) occurred in 67.6% of patients in the Japanese phase I/II trials of GnP therapy, and is often a limiting factor. The purpose of this study was to identify the risk factors for severe neutropenia in pancreatic patients receiving GnP therapy in clinical settings. Methods: A retrospective study of 222 consecutive patients with pancreatic cancer who received GnP therapy at the Cancer Institute Hospital from December 2014 to December 2016 was conducted. Univariate and multivariate analyses were used to compare blood test values and patients’ characteristics between patients with no neutropenia or Grade 1/2 (non-serious) neutropenia and those with Grade ≥ 3 (severe) neutropenia. Results: There were 19 patients (8.6%) with modified FOLFIRINOX in the previous treatment history. The median doses of nab-paclitaxel and gemcitabine were 192.5 mg (range 134-277.5) and 1,545 mg (range 1,000-2,220), respectively. Severe neutropenia and febrile neutropenia occurred in 118 patients (53.2%) and 15 patients (6.8%), respectively. Multivariate logistic regression analysis indicated that ANC (absolute neutrophil count) &lt; 3.03 x 103 /μL (OR: 4.806, 95% CI: 2.416-9.558, p = 0.000), T-Bil ≥ 0.6 mg/dl (OR: 1.964, 95% CI: 1.040-3.708, p = 0.037) and CRP &lt; 0.13 mg/dl (OR: 2.607, 95% CI: 1.331-5.106, p = 0.005) were significant risk factors for severe neutropenia. The incidence rate of severe neutropenia was 85.7% (18/21) in patients with all three identified factors, while it was 27.7% (13/47) in patients with none of them. Age was not a risk factor in either univariate or multivariate analysis. Conclusions: Low ANC, high T-Bil, and low CRP were found to be risk factors for severe neutropenia in patients receiving GnP therapy. It would be desirable to monitor patients with these risk factors carefully, even if their values are within the standard ranges.

High total bilirubin level is a significant risk factor for severe neutropenia in patients receiving irinotecan-based chemotherapy.

Irinotecan is effective for the treatment of metastatic colorectal cancer (mCRC) and advanced pancreatic cancer (aPC). However, these treatments are often limited due to the incidence of severe neutropenia. We identified risk factors for severe neutropenia in patients with mCRC or aPC, receiving irinotecan-based chemotherapy regimens. The study selected 104 patients (mCRC: 53 and aPC: 51) who received irinotecan-based chemotherapy between January 2014 and May 2018 and who were included in the present study. The initial dose of irinotecan was 150mg/m2 in all patients, and patients with a lower initial dose of irinotecan were excluded. Severe neutropenia (grade ≥ 3) occurred in 56 patients (53.8%). Multivariable Cox proportional hazards analysis indicated that modified FOLFIRINOX (mFOLFIRINOX) and serum total bilirubin (T-Bil) were significant risk factors for severe neutropenia. Moreover, with receiver-operating characteristic (ROC) curve analysis, the cutoff for T-Bil was found to be 0.7mg/dL. Among patients treated with mFOLFIRINOX therapy, the incidence of severe neutropenia was significantly higher in patients with high level of T-Bil (> 0.7mg/dL) than in those without it (93.8% vs 55.0%, P = 0.006). A chemotherapy regimen (modified FOLFIRINOX therapy) and T-Bil > 0.7mg/dL were significant risk factors for severe neutropenia in patients receiving 150mg/m2 irinotecan.

Risk factors for severe neutropenia induced by combination therapy of S-1 and cisplatin in patients with advanced/recurrent gastric cancer.

S-1 and cisplatin therapy (SP therapy) is widely used as the first-line of advanced/recurrent gastric cancer. However, severe neutropenia is often observed (40%) during this therapy. Therefore, the risk management of neutropenia is important. From September 2014 to April 2017, we investigated 76 patients who underwent SP therapy as primary treatment for advanced/recurrent gastric cancer at Ogaki Municipal Hospital. Risk factors for grade 3/4 neutropenia were examined by univariate and multivariate analyses. In SP therapy, 19 patients (25%) experienced grade 3/4 neutropenia. The results of multivariate analysis of factors with p <0.05 in the univariate analysis indicated that less than 10.6 g/dL of the haemoglobin value before the course at the lowest neutrophil count (odds ratio: 7.900; 95% CI: 1.280-48.60; p = 0.026), more than six courses of the total course (odds ratio: 9.13; 95% CI: 2.13-39.1; p = 0.003), and less than 3140 m2 neutrophil counts (odds ratio: 5.33; 95% CI: 1.47-19.3; p = 0.011) before chemotherapy were risk factors of grade 3/4 neutropenia. A low haemoglobin value before the course at the lowest neutrophil count was revealed as a risk factor causing severe neutropenia in SP therapy.

Examination of multiple UGT1A and DPYD polymorphisms has limited ability to predict the toxicity and efficacy of metastatic colorectal cancer treated with irinotecan-based chemotherapy: a retrospective analysis

BackgroundTo evaluate a new UGT1A and DPYD polymorphism panel to better predict irinotecan-induced toxicity and the clinical response in Chinese patients with metastatic colorectal cancer (mCRC).MethodsThe genotypes of UGT1A (UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A7*4 and UGT1A9*22) and DPYD (DPYD*5, DPYD c.1896 T > C, and DPYD*2A) were examined by direct sequencing in 661 mCRC patients receiving irinotecan-based chemotherapy. The influences of UGT1A and DPYD polymorphisms on severe irinotecan-induced toxicities and clinical outcomes were assessed.ResultsIn the cohort studied here, the incidence of UGT1A1*6, UGT1A1*28, UGT1A7*2, UGT1A7*3, UGT1A9*22, DPYD*5, and DPYD c.1896 T > C variants were 34.8%, 24.2%, 34.3%, 39.4%, 81.8%, 48.4% and 20.4%, respectively. UGT1A1*27 and DPYD*2A had low frequencies and UGT1A7*4 was not found. A total of 59 patients (8.9%) suffered severe diarrhea and 136 patients (20.6%) suffered severe neutropenia. UGT1A1*28 heterozygotes (OR = 2.263, 95%CI 1.395–3.670), UGT1A1*28 homozygotes (OR = 5.910, 95%CI 1.138–30.672) and UGT1A1*6 homozygotes (OR = 4.737, 95%CI 1.946–11.533) were independent risk factors for severe neutropenia. UGT1A polymorphisms were not found to relate to severe diarrhea. DPYD*5 was determined to be an independent risk factor for severe diarrhea (OR = 2.143, 95%CI 1.136–4.041). Neither DPYD*5 nor DPYD c.1896 T > C was found to relate to severe neutropenia. In the first-line irinotecan-based treatment, UGT1A1*28 and DPYD*5 contributed to higher response rates (P = 0.043 and P = 0.019, respectively), while DPYD*5 was found to associate with better progression-free survival (P = 0.015). UGT1A1*27 contributed to worse overall survival (P < 0.001).ConclusionResults still showed UGT1A1*6 and UGT1A1*28 to be partially associated with irinotecan-induced toxicity and clinical response. An examination of more UGT1A loci, except for UGT1A1*6 and UGT1A1*28, was not helpful to improve the predictive value of irinotecan-based toxicity and efficacy. An examination of DPYD*5 assisted in the prediction of severe diarrhea.

Co-administration of dexamethasone increases severity and accelerates onset day of neutropenia in bladder cancer patients on methotrexate, vinblastine, adriamycin and cisplatin chemotherapy: a retrospective cohort study

BackgroundBladder cancer patients receiving methotrexate, vinblastine, adriamycin and cisplatin (MVAC) chemotherapy are co-administered with dexamethasone as an anti-emetic. We examined whether or not dexamethasone affects the severity and onset day of MVAC-induced severe neutropenia.MethodsThis was a retrospective study of bladder cancer patients treated with MVAC chemotherapy with or without dexamethasone as an antiemetic at Kanazawa University Hospital during January 2005 - December 2009. Patients were categorized into three groups; no dexamethasone use (Dex (−)), dexamethasone on day 2 (Dex 1 day), and dexamethasone on days 2, 3 and 4 (Dex multiday). We evaluated the incidence of grade 3/4 neutropenia and the day of onset of first severe neutropenic episode during the first course of MVAC chemotherapy. Logistic regression was used to investigate whether co-administration of dexamethasone was a risk factor for severe neutropenia.ResultsEpisodes of grade 3/4 neutropenia occurred in 3 out of 6 (50.0%), 11 out of 12 (91.7%) and 6 out of 6 (100%) patients in the Dex (−), Dex 1 day, and Dex multiday groups, respectively. The appearance day of first severe neutropenia in the Dex multiday group (13.2 ± 1.0) was significantly accelerated compared to the Dex (−) group (17.7 ± 2.1). Univariate logistic regression analysis revealed that dexamethasone is a risk factor for severe neutropenia (OR 17.0; 95%CI: 1.3–223.1).ConclusionsCo-administration of dexamethasone for anti-emesis brings forward the first appearance of neutropenia, and increases the severity of neutropenia, in bladder cancer patients receiving MVAC chemotherapy.

Development of a Nomogram for Predicting Severe Neutropenia Associated With Docetaxel-Based Chemotherapy in Patients With Castration-Resistant Prostate Cancer

BackgroundNeutropenia is a major adverse event of docetaxel-based chemotherapy. The present study was undertaken to evaluate the incidence of neutropenia and to develop a nomogram for predicting Grade 4 neutropenia during the first cycle of docetaxel-based chemotherapy in patients with castration-resistant prostate cancer (CRPC). Patients and MethodsThis study included 112 patients with CRPC treated with docetaxel-based systemic chemotherapy. We evaluated the incidence and risk factors for Grade 4 neutropenia in the first cycle of chemotherapy. ResultsSixty-two of 112 patients (55.4%) developed Grade 4 neutropenia in the first cycle of docetaxel-based chemotherapy. There were significant differences in age, baseline white blood cell count, and baseline neutrophil count between patients with non-Grade 4 neutropenia and those with Grade 4 neutropenia in univariate analyses. The serum prostate-specific antigen level, hemoglobin level, creatinine, albumin, Eastern Cooperative Oncology Group performance status, metastatic sites, extent of disease, and history of external beam radiotherapy to the prostate were not significantly different between the 2 groups. Multivariate logistic regression analysis showed that age (odds ratio [OR], 1.08; P = .019) and baseline neutrophil counts (OR, 0.79; P = .045) were significant independent risk factors for severe neutropenia. A nomogram and a calibration plot on the basis of these results were developed from a multivariate logistic regression analysis to predict the probability of Grade 4 neutropenia. ConclusionAge and baseline neutrophil counts were significant independent risk factors for Grade 4 neutropenia. The nomogram to predict it provides useful information for the management of patients with CRPC treated with docetaxel chemotherapy.

Risk factors for severe neutropenia following intra-arterial chemotherapy for intra-ocular retinoblastoma.

PurposeIntra-arterial chemotherapy is a promising strategy for intra-ocular retinoblastoma. Neutropenia is the most commonly encountered systemic toxicity and in this study we aimed to determine the risk factors associated with the development of severe (≥grade 3) neutropenia.MethodsRetrospective review of 187 evaluable cycles of melphalan-containing intra-arterial chemotherapy from the first three cycles administered to 106 patients with intra-ocular retinoblastoma from May 2006 to June 2011. Cycles were considered to be evaluable if (1) blood count results were available in the 7 to 14 days post-treatment interval and (2) concurrent intravenous chemotherapy was not administered. Toxicity was assessed via the Common Terminology Criteria for Adverse Events version 4.0.Results54 cycles (29%) were associated with grade 3 (n = 43) or grade 4 (n = 11) neutropenia. Multivariate stepwise logistic regression revealed that a higher melphalan dose (>0.40 mg/kg) was significantly associated with severe neutropenia during all 3 cycles (odds ratio during cycle one 4.11, 95% confidence interval 1.33–12.73, p = 0.01), but the addition of topotecan and/or carboplatin were not. Prior treatment with systemic chemotherapy was not associated with severe neutropenia risk in any analysis.ConclusionsIntra-arterial melphalan-based chemotherapy can cause severe neutropenia, especially when a dose of greater than 0.40 mg/kg is administered. Further study with a larger sample may be warranted.

Analysis of the Risk Factors for Severe Neutropenia in Advanced Non-Small Cell Lung Cancer after the First Course of Chemotherapy with Third-Generation Agents

We retrospectively evaluated clinical data before therapy to determine the risk factors for severe neutropenia in advanced non-small-cell lung cancer (NSCLC) patients treated with third-generation agents. We analyzed 100 patients who received such agents (paclitaxel, docetaxel, gemcitabine, irinotecan, or vinorelbine) for advanced NSCLC. The endpoint of the survey was the occurrence of severe neutropenia (grade 4). Risk factors significantly related to severe neutropenia were identified using logistic regression analysis. Of the 100 patients studied, the median age was 62.0 (32-81 years), and 77 (77.0%) were male. CEA 6.6 (0-2220) ng/dL and cytokeratin 19 fragment 21-1 (CYFRA) 4.8 (0.2-173.8) ng/dL before chemotherapy were higher than normal range. Severe neutropenia occurred in 36.0%, the incidence being highest in the first cycle (61.1%). In the univariate analysis, variables associated with severe neutropenia were sex, chest pain, absolute neutrophil count (ANC), Cr, CRP, and CYFRA. In the multivariate analysis, low CYFRA level was identified as a significant risk factor that contributed independently to chemotherapy-induced severe neutropenia (p<0.05). Our analysis suggests that low CYFRA level is the most important risk factor for severe neutropenia in advanced NSCLC patients after the first course of chemotherapy with third-generation agents.

AOS29 Predictive factors for severe neutropenia after the first chemotherapy cycle in patients with breast cancer

Background Neutropenia after chemotherapy can frequently lead to a life-threatening infection. Unexpected episodes of neutropenia can occur after the first cycle of chemotherapy. We sought to characterise predictive risk factors for severe neutropenia in patients with breast cancer after the first cycle of chemotherapy. Methods We prospectively collected data for patients with breast cancer who received the doxorubicin and cyclophosphamide (AC) regimen for any stage at the oncology unit during January to December 2011. Patients who received primary CSF prophylaxis were not included. The correlation between patient’s demography, breast cancer history, blood chemistry, and occurrence of severe neutropenia and febrile neutropenia (FN) were analysed. Findings Seventy-five patients with breast cancer were included in this study. Their mean age was 49 years (SD ± 9). Most patients (98.9%) had a good performance status. None had received previous chemotherapy or radiotherapy. There were a few patients with comorbidities, including 1% with type 2 diabetes mellitus, and 19% with hypertension. 4% of the breast cancers were metastatic to the lung and bone. The mean body surface area was 1.59 m 2 . All patients had normal baseline white blood cell counts. After the first cycle of AC, 84% and 60% of patients developed grade 3 and 4 neutropenia, respectively, which turned into FN in 20% of patients. Analyses of predictive factors showed no statistically significant correlation between grade 4 neutropenia and age greater than 60 years (RR 0.95, 95% confidence interval (CI) 0.49–2.06), bovine serum albumin (BSA) less than 1.45 m 2 (RR 1.10, 95% CI 0.73–1.67), underweight for body-mass index less than 18.5 kg/ m 2 (RR 1.0, 95% CI 0.48–2.1), dietary protein index less than 0.5 g/kg/day (RR 1.05, 95% CI 0.50–2.22), and non-metastatic disease (RR 0.896, 95% CI 0.39–2.04). Interpretation Simple clinical factors cannot be used to reliably predict the risk of FN in patients with breast cancer during the first cycle of chemotherapy with AC. For development of future predictive models, the complex relation within datasets should be taken into account such as novel biomarkers or genetic profiles. The authors declared no conflicts of interest.

UGT1A1*28 Genotype and Irinotecan-Induced Neutropenia: Dose Matters

The Food and Drug Administration and Pfizer changed the package insert for irinotecan to include a patient's UGT1A1*28 genotype as a risk factor for severe neutropenia on the basis of the findings of four pharmacogenetic studies, which found that irinotecan-treated patients who were homozygous for the UGT1A1*28 allele had a greater risk of hematologic toxic effects than patients who had one or two copies of the wild-type allele (UGT1A1*1). Findings of subsequent irinotecan pharmacogenetic studies have been inconsistent. In a meta-analysis, we reviewed data presented in nine studies that included a total of 10 sets of patients (for a total of 821 patients) and assessed the association of irinotecan dose with the risk of irinotecan-related hematologic toxicities (grade III-IV) for patients with a UGT1A1*28/*28 genotype. The risk of toxicity was higher among patients with a UGT1A1*28/*28 genotype than among those with a UGT1A1*1/*1 or UGT1A1*1/*28 genotype at both medium (odds ratio [OR] = 3.22, 95% confidence interval [CI] = 1.52 to 6.81; P = .008) and high (OR = 27.8, 95% CI = 4.0 to 195; P = .005) doses of irinotecan. However, risk was similar at lower doses (OR = 1.80, 95% CI = 0.37 to 8.84; P = .41). Low doses of irinotecan (100-125 mg/m2) are in the commonly used therapeutic range. The risk of experiencing irinotecan-induced hematologic toxicity for patients with a UGT1A1*28/*28 genotype thus appears to be a function of the dose of irinotecan administered.

Irinotecan-induced neutropenia and UGT1A1*28: Does dose matter?

4023 Background: On July 7 2005, the Food and Drug Administration (FDA) of the U.S.A. and Pfizer Pharmaceuticals changed the package insert information for irinotecan to include a patient’s UGT1A1*28 genotype as a risk factor for severe neutropenia. This change resulted from the findings of four pharmacogenetic studies that identified a 2.5 to 17-fold risk of toxicity in homozygous UGT1A1*28 patients receiving irinotecan. Notably, a total number of 34 patients in the four studies were homozygous for the UGT1A1*28 allele. Subsequent studies on larger patient cohorts treated with other dosage regimens have failed to consistently replicate the UGT1A1*28 genotype-toxicity associations, thus confounding the development of dosing recommendations. This has contributed to confusion on how best to select a safe dose of irinotecan for a patient who is homozygous for UGT1A1*28. Methods: We reviewed the data presented in ten irinotecan pharmacogenetic studies (825 patients) and assessed the correlations between the incidence of irinotecan-induced hematological toxicities (grade III/IV) in UGT1A1*28/*28 patients, irinotecan dose, and overall toxicity. Results: We found that the incidence of grade III/IV hematological toxicities in UGT1A1*28/*28 patients was positively related to both irinotecan dose (Spearman Rank correlation rS=0.68; P=0.04; N=10 studies) and the overall incidence of toxicity of a regimen (rS=0.88; P=0.002; N=10 studies). The incidence of severe hematological toxicity amongst all patients was not related to irinotecan dose (rS=0.44; P=0.20, N=10 studies). Conclusions: Our results suggest that the risk of experiencing irinotecan-induced hematological toxicity for UGT1A1*28/*28 patients is a function of the dose of irinotecan administered. In the spirit of maximizing patient safety, we support the use of genotype-based dosing of irinotecan for high doses of irinotecan, but believe it may not be as useful for lower doses and suggest strategies for dosing patients with irinotecan. [Table: see text] No significant financial relationships to disclose.