Granulocyte Colony-stimulating Factor Prophylaxis Research Articles

Chemotherapy-induced febrile neutropenia (FN) and FN prevention strategies in cancer care in the U.S. Veterans Health Administration (VHA).

6608 Background: Chemo-induced FN can be a life-threatening adverse event requiring immediate hospitalization and is associated with increased infection-related mortality and healthcare costs. Because the VHA has a fully-integrated national claims database, we used this database to assess FN incidence, burden, and prevention strategies in VA cancer patients. Methods: VHA’s database includes de-identified inpatient, outpatient, pharmacy, and laboratory claims and EMR data. Patients ≥ 18 years old with lung, colorectal (CRC), or prostate cancer or non-Hodgkin lymphoma (NHL) who had initiated ≥ 1 course of myelosuppressive chemo from Jan 2006–Sept 2011 were included. Endpoints included chemo treatment patterns and FN incidence, burden (inpatient mortality, length of stay [LOS], and costs), and prophylaxis. FN was identified based on ICD-9-CM codes for neutropenia. Prophylaxis was defined as first use of any granulocyte colony-stimulating factor (G-CSF) or intravenous antibiotics within 5 days of chemo administration or oral antibiotics within 7 days before and 6 days after chemo administration in any cycle. Costs were estimated using hospital and laboratory claims containing an FN diagnosis. Results: 27,899 patients were eligible and were included in the analysis. Most were ≥ 65 years old (56%) and male (98%). See Table for selected endpoints. Conclusions: FN was a common event, and patients with FN had lengthy hospital stays, high inpatient mortality rates, and considerable costs. In the VHA, antibiotic prophylaxis was generally used more frequently than G-CSF prophylaxis. [Table: see text]

Interim safety analysis of a compassionate-use program (CUP) and early-access program (EAP) providing cabazitaxel (Cbz) plus prednisone (P) to patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) previously treated with docetaxel.

5055 Background: Cbz + P provides a significant survival benefit vs mitoxantrone + P in pts with mCRPC (Phase III TROPIC study [NCT00417079]; hazard ratio 0.70; p < 0.0001). These findings supported the initiation of ongoing Sanofi-funded CUP and EAP (NCT01254279) to provide access to Cbz prior to commercialization and to collect real-life safety data. Methods: Expected enrollment is ~1600 pts with mCRPC from 250 centers worldwide. Pts receive Cbz (25 mg/m2 Q3W) + P (10 mg oral QD) until progressive disease (PD), death, unacceptable toxicity, physician/pt decision or Cbz commercial availability. Pts are followed until 30 days after last dose. Granulocyte colony-stimulating factor (G-CSF) use is recommended as per ASCO guidance. Results: Interim baseline and safety data from the first 1301 pts treated in 37 countries are now available. Mean age was 68 yrs (22% were ≥ 75 yrs). All pts had an ECOG performance status ≤ 2. Median time from initial prostate cancer diagnosis was 57.6 months and 60% of pts had ≥ 2 metastatic sites; the most common were bone (91%) and lymph nodes (regional 30%, distant 27%). In total, 17% had PD whilst on docetaxel. The median number of Cbz cycles was 6 (range 1–22); median relative dose intensity was 99%. Overall, 837 pts (64%) received G-CSF (n = 123 curative [C], n = 765 prophylactic [P] and n = 99 [C + P]). Of 1142 pts (88%) who discontinued Cbz + P, the most common reasons were PD (44%), adverse event (AE; 27%), physician decision (13%) and commercial availability of Cbz (7%). Grade 3–4 AEs possibly related to Cbz + P occurred in 43% of pts; the most frequent were clinical neutropenia (18%), febrile neutropenia (FN; 7%) and diarrhea (4%). Of 80 pts (6%) with AEs leading to death, the AE was related to Cbz + P in 39 pts (3%). Conclusions: These results provide valuable data on Cbz + P treatment in routine clinical practice, confirming the safety results of clinical trials and showing that treatment with Cbz + P is associated with a manageable safety profile. The incidence of FN seems slightly lower than in TROPIC, owing to more frequent use of G-CSF prophylaxis in the CUP and EAP. Clinical trial information: NCT01254279.

Effectiveness of supportive care measures to reduce infections in pediatric AML: a report from the Children's Oncology Group

AbstractObjective was to describe the effect of antibiotic and granulocyte colony-stimulating factor (G-CSF) prophylaxis and discharge policy on infection risk and nonrelapse-related mortality (NRM) during chemotherapy for children with acute myeloid leukemia. Patients were non–Down syndrome children enrolled on Children's Oncology Group (COG) trial AAML0531. We surveyed sites to determine institutional standards for systemic antibacterial, antifungal, and G-CSF prophylaxis, and mandatory hospitalization during neutropenia. COG institution survey response rate was 180 of 216 (83.3%). Of 1024 patients enrolled on AAML0531, 897 were non-Down patients from survey-responding institutions. In multiple regression, antibacterial prophylaxis reduced any sterile-site bacterial infection (incidence rate ratio [IRR] 0.85; 95% confidence interval [CI], 0.72-1.01; P = .058) and Gram-positive sterile-site infection (IRR 0.71; 95% CI, 0.57-0.90; P = .004). Prophylactic G-CSF reduced bacterial (IRR 0.79; 95% CI, 0.67-0.92; P = .004) and Clostridium difficile infections (CDIs; IRR 0.46; 95% CI, 0.25-0.84; P = .012). Mandatory hospitalization did not reduce bacterial/fungal infection or significantly reduce NRM but did increase CDI (IRR 1.96; 95% CI, 1.34-2.87; P < .001). Antibacterial and G-CSF prophylaxis reduced infection rates while mandatory hospitalization did not reduce infection or significantly affect NRM. This trial was registered at www.clinicaltrials.gov as #AAML0531.

Neutropenia and G-CSF in lymphoproliferative diseases

BackgroundChemotherapy-induced neutropenia is a major cause of morbidity and mortality. It frequently causes dose reductions or treatment delay, which can be prevented or treated by the administration of granulocyte-colony-stimulating factor (G-CSF). However, a better knowledge of the incidence, day of onset after therapy, and duration of neutropenia is essential to optimize the use of G-CSF.Design and methodsSix hundred and ninety-four patients from a single institution, affected by lympho-proliferative diseases, were retrospectively reviewed for the occurrence of grade 4 neutropenia and febrile neutropenia (FN). Duration of neutropenia and time of neutrophil nadir were also retrieved. The diagnoses included non-Hodgkin's lymphoma, Hodgkin's lymphoma, and multiple myeloma. Chemotherapy regimens were obviously different according to the diagnosis, disease stage, and first or subsequent lines of therapy.ResultsNo patient received G-CSF as primary prophylaxis. Median nadir did not significantly differ among patients treated with first or successive lines of therapy. The incidence of grade 4 neutropenia and FN ranged from 0 to 94%, depending on the chemotherapy regimen. Patients receiving a first-line chemotherapy regimen had a significantly lower incidence of febrile grade 4 neutropenia compared to patients treated with a second or subsequent line of therapy. The duration of grade 4 neutropenia was significantly longer in patients given second or subsequent lines.ConclusionThe results of this study could be useful to define the nadir onset in the hematologic setting in order to correctly tailor timing and duration of G-CSF prophylaxis and to assess the lowest fully effective dose.

Primary Granulocyte Colony-Stimulating Factor Prophylaxis During the First Two Cycles Only or Throughout All Chemotherapy Cycles in Patients With Breast Cancer at Risk for Febrile Neutropenia

Early breast cancer is commonly treated with anthracyclines and taxanes. However, combining these drugs increases the risk of myelotoxicity and may require granulocyte colony-stimulating factor (G-CSF) support. The highest incidence of febrile neutropenia (FN) and largest benefit of G-CSF during the first cycles of chemotherapy lead to questions about the effectiveness of continued use of G-CSF throughout later cycles of chemotherapy. In a multicenter study, patients with breast cancer who were considered fit enough to receive 3-weekly polychemotherapy, but also had > 20% risk for FN, were randomly assigned to primary G-CSF prophylaxis during the first two chemotherapy cycles only (experimental arm) or to primary G-CSF prophylaxis throughout all chemotherapy cycles (standard arm). The noninferiority hypothesis was that the incidence of FN would be maximally 7.5% higher in the experimental compared with the standard arm. After inclusion of 167 eligible patients, the independent data monitoring committee advised premature study closure. Of 84 patients randomly assigned to G-CSF throughout all chemotherapy cycles, eight (10%) experienced an episode of FN. In contrast, of 83 patients randomly assigned to G-CSF during the first two cycles only, 30 (36%) had an FN episode (95% CI, 0.13 to 0.54), with a peak incidence of 24% in the third cycle (ie, first cycle without G-CSF prophylaxis). In patients with early breast cancer at high risk for FN, continued use of primary G-CSF prophylaxis during all chemotherapy cycles is of clinical relevance and thus cannot be abandoned.

Transdermal Oestradiol in the Management of Castration-resistant and Corticosteroid-resistant Prostate Cancer — a Dose Escalation Study

s / Clinical Oncology 25 (2013) e67ee74 e72 [1]. Prophylactic use of granulopoiesis-stimulating factors, such as granulocyte-colony-stimulating factor (G-CSF), is being increasingly used to prevent chemotherapy-induced neutropaenia [2e4]. To compare the rate of febrile neutropaenia before and after implementation of G-CSF prophylaxis in patients receiving chemotherapy for testicular cancer. To determine the impact of these events on unscheduled care. Materials andmethods: Over an 18month period, we prospectively audited the incidence of febrile neutropaenia before (n 1⁄4 12) and after (n 1⁄4 8) implementation of prophylactic pegylated G-CSF (6mg SC 24 h post-chemotherapy) in patients receiving comparable chemotherapy regimens. Identification of febrile neutropaenic episodes and resultant impact on treatment recorded. There were no significant differences in chemotherapy regimens or other supportive care apart from the use of G-CSF. Results: The rate of neutropaenic sepsis was significantly different between the pre-GCSF and post-GCSF group (42% versus 0%, P 1⁄4 0.05). In the pre-GCSF group, 4 patients developing febrile neutropaenia went on to have G-CSF with subsequent cycles. Those developing febrile neutropaenia in the preGCSF group had a cumulative 31 days of unscheduled inpatient stay. This included one patient admitted to intensive care. There were no unscheduled inpatient stays in the post-GCSF group. Conclusion: Use of prophylactic G-CSF following chemotherapy for testicular cancer significantly reduces the incidence of febrile neutropaenia and subsequent inpatient stays.

Chemotherapy (CT) treatment patterns and neutropenia management in gastric cancer patients (pts) receiving myelosuppressive chemotherapy in Europe.

128 Background: Granulocyte-colony stimulating factor (G-CSF) primary prophylaxis (PP) is recommended for pts undergoing CT who are at overall high risk for febrile neutropenia (FN). No single CT regimen is recognized as standard in gastric cancer and few regimens are represented in G-CSF guidelines. We therefore evaluated neutropenia management in pts receiving CT for gastric cancer. Methods: This was a multicentre prospective observational study that enrolled pts sequentially from 11/2009 to 06/2011. Adult gastric cancer pts (any stage) with ≥3 cycles of myelosuppressive CT scheduled and an investigator-assessed overall FN risk ≥20% were eligible. The primary outcome was the proportion of pts who received PP G-CSF (G-CSF in days 1-7 of cycle 1). Secondary outcomes included FN incidence, chemotherapy administration, and G-CSF use. Posthoc analyses investigated the subgroup who received DCF, including modifications from standard DCF (Van Cutsem. JCO. 2006), and the G-CSF support given up to the first FN (G-CSF prophylaxis given per label in each cycle up to that in which FN occurred). Results: Of 209 pts enrolled, 199 were eligible and their data analyzed. The mean (±SD) age was 62 (±12) years, 76% were male, 17% were ECOG 2 and none ECOG 3-4; 47% were treatment naïve. Planned CT was palliative in 74% of pts; overall, 27 different backbone regimens were planned (10 triplet, 12 doublet, 5 single drug regimens). The most common regimen used was DCF (54 pts, 27%), predominantly given as modified DCF (41 pts). Despite being assessed as high risk for FN, G-CSF PP was administered to only 35% of pts overall (n=70; 54 pegfilgrastim, 16 daily G-CSF) and to 69% of pts who received DCF. FN occurred in 14 pts (10%), 9 of whom received DCF. A large majority of FN pts (12/14, 86%) had not received prophylactic G-CSF per label up to the first FN occurrence; furthermore, 86% of FN pts did not receive G-CSF prophylaxis in the cycle following the FN event. Conclusions: The variety of CT used, frequent modifications to standard CT, and presence of pt risk factors makes FN risk estimation difficult in gastric cancer. Improved risk assessment and appropriate targeting of G-CSF PP to high risk pts is needed.

Toxicity and quality of life of Korean breast cancer patients treated with docetaxel-containing chemotherapy without primary G-CSF prophylaxis

The aim of this study was to evaluate the toxicity and quality of life (QoL) of breast cancer patients treated with a docetaxel-containing chemotherapeutic regimen and to compare adriamycin and cyclophosphamide (AC) for four cycles followed by docetaxel (D) for four cycles with docetaxel, adriamycin, and cyclophosphamide (TAC) for six cycles without primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. Node-positive breast cancer patients who received surgery from three hospitals were included. Subjects received docetaxel-containing chemotherapy and completed a questionnaire on QoL (EORTC QLQ-C30 and QLQ-BR23) at each cycle. Toxicity was assessed using the National Cancer Institute Common Toxicity Criteria. All 78 eligible subjects and 542 cycles were analyzed. The incidence of dose reduction and grade 3 edema was higher in the AC-D group. The incidence of febrile neutropenia was significantly increased in the TAC group (63.4 %) compared to the AC-D group (29.7 %). Grade 3 or 4 anemia was higher in the TAC group, and grade 3 or 4 arthralgia was higher in the AC-D group. There were no significant differences in severe nausea and vomiting, fatigue, neuropathy, and peripheral edema. Baseline quality of life showed no difference between the two groups. The global health status decreased during chemotherapy and recovered to baseline level 3 months after chemotherapy. Although the incidence of febrile neutropenia was high without primary G-CSF prophylaxis and was more severe in the TAC group, QoL revealed comparable results in both regimens; therefore, it could be one of the considerations in the choice of treatment strategy.

Abstract P1-15-10: Chemotherapy-Induced Neutropenia in Breast Cancer Patients Receiving Sequential Anthracycline and Taxane Chemotherapy: An institutional experience

Abstract Background: Sequential regimen of anthracyclines and taxanes are commonly used in patients with early stage breast cancer (BC) and curative treatment intent. Due to the associated myelotoxicity, internationally accepted guidelines recommend granulocyte-colony stimulating factors (G-CSF) as primary or secondary prophylaxis, dependent on chemotherapy (CT) and patient-associated risk of febrile neutropenia. As part of a quality control initiative at our center, we have analyzed rates of grade 1 or 2 (&amp;lt;2.0 to &amp;gt;1.0 × 109/L) and 3 or 4 (&amp;lt;1.0 to &amp;lt;0.5 × 109/L) neutropenia, febrile neutropenia (&amp;lt;0.5 × 109/L and single oral temperature ≥38.3°C/100.4°F), CT dose reductions, anti-infective use, and hospitalizations in cycles with pegfilgrastim prophylaxis. Methods: Patients (pts) with BC stages I to III received four three-weekly (q21) cycles of adjuvant or neoadjuvant EC (Epirubicin 90 mg/m2 + Cyclophosphamide 600 mg/m2 q21) followed by four cycles of D (Docetaxel 100 mg/m2 q21) plus primary or secondary pegfilgrastim prophylaxis. Chart records were collected and analyzed retrospectively for patients treated between 2009 and 2012 at our institution for incidence of neutropenia and for the presence of neutropenia-associated risk factors. Only cycles with pegfilgrastim prophylaxis were considered for this analysis. Results: 100 consecutive patients were identified who had overall received 200 EC cycles followed by 251 D cycles under G-CSF prophylaxis with pegfilgrastim. Pts age mean: 51,57 (SD:11,23), BMI mean: 25,8 (SD:5,03) were well controlled in both sequences. Overall, neutropenia was significantly higher for EC (p = 0.001), however higher grade neutropenia (Grade3 and 4) were comparable (p = 0.200). No statistically significant correlations were found between neutropenia and age or body mass index. Conclusions: Sequential use of EC followed by D in combination with prophylactic pegfilgrastim results in lower den expected FN rate [1]. In contrast to most published trials EC leads to significantly more neutropenias than D. However, the use of pegfilgrastim reduces both EC and D associated neutropenias grade 3 and 4 to a similar extent.

Abstract P1-15-01: Patterns of granulocyte colony stimulating factor (G-CSF) use in elderly breast cancer (BC) patients receiving myelosuppressive chemotherapy

Abstract Background: Febrile neutropenia (FN) is a common and potentially serious complication of myelosuppressive chemotherapy treatment in cancer patients. Oncology guidelines recommend primary G-CSF prophylaxis (PPG) in patients with a high risk of developing FN, which is risk &amp;gt;20% based on myelotoxicity of the regimen itself or from a combination of the therapy, older age, comorbidities and disease characteristics (Lyman Cancer 2011). Current patterns of G-CSF use and FN occurrence among elderly patients receiving myelosuppressive chemotherapy for BC have not been previously reported. To determine this, we performed a retrospective analysis using a subset of the Medicare 5% database. Methods: The Medicare 5% claims data set (includes a representative 5% systematic sample of Medicare beneficiaries) was used to identify BC patients age 65+ initiating chemotherapy between 7/1/2003 and 6/30/2009. Chemotherapy courses were identified for each patient; only the first course was used for this analysis. Using the National Comprehensive Cancer Network guidelines on Myeloid Growth Factors (NCCN V1.2012), chemotherapy course regimens were classified as high risk (HR) or intermediate risk (IR) for FN. Duration of first cycle was from date of first chemotherapy claim to the chemotherapy claim at day 21 or later, which defined the first day of the second cycle, etc., to a maximum of 9 cycles. First administration of G-CSF [filgrastim (NEUPOGEN®) or pegfilgrastim (Neulasta®)] was classified as either PPG (within first 5 days of first cycle), secondary prophylaxis (within first 5 days of second or subsequent cycles), or reactive (day 6 or later of first or subsequent cycles). FN assessed during the chemotherapy course was defined as hospitalization with a code for neutropenia in any position. Results: 885 courses with high FN risk and 1046 with IR FN risk were identified. The HR cohort was younger (71.4 vs 74.5 yrs) and had fewer comorbidities than the IR cohort. Selected aspects of G-CSF use patterns are summarized in the table. Among HR courses, 11.8% had ≥1 FN hospitalization and 2.1% had 2+; among IR courses 5.6% had ≥1 and 0.4% had 2+. Conclusion: NCCN recommends PPG be used with HR regimens and older age (notably &amp;gt;65 yr), an important risk factor for developing severe neutropenic complications. Despite this, PPG was used for elderly breast cancer patients in only 52% of chemotherapy courses with high risk of FN and in 10% of IR courses. More than 10% of patients with a HR regimen had an FN hospitalization. Careful attention to FN risk factors, including regimen and patient age, is needed when planning treatment strategy. HR regimens: TAC (389); dose dense AC→T (345); docetaxel+trastuzumab (61); doxorubicin+docetaxel (50); doxorubicin+paciltaxel (21); docetaxel q14(19). IR regimens: CMF classic (481); paclitaxel q21 (337); docetaxel q21 (94); paclitaxel+ trastuzumab (87); FEC (47). Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P1-15-01.

Neutropenia‐Associated Outcomes in Adults with Acute Myeloid Leukemia Receiving Cytarabine Consolidation Chemotherapy with or without Granulocyte Colony‐Stimulating Factor

To determine whether granulocyte colony-stimulating factor (G-CSF) prophylaxis after consolidation with high- or intermediate-dose cytarabine (H/IDAC) for treatment of acute myeloid leukemia (AML) reduces the frequency of neutropenia-associated complications. Retrospective medical record review. Academic medical center. Seventy-eight patients aged 18 years or older in whom H/IDAC consolidation chemotherapy was initiated for consolidation of AML between November 2004 and November 2010. Patient demographic data, information on the hospitalization for consolidation, data on G-CSF use after H/IDAC chemotherapy, and details on any readmissions were collected. Patients were deemed to have received G-CSF prophylaxis if there was documentation of the intent for use of either filgrastim or pegfilgrastim. Outcome data also were collected, including dates of relapse or second induction treatment course, and death or last follow-up visit. We compared data based on patient receipt of G-CSF (G-CSF vs no G-CSF) after each chemotherapy cycle. We assessed differences in the duration of hospitalization, fever, intravenous antibiotic use, and neutropenia, as well as rate of documented infections, time to disease recurrence, and overall survival. Compared with no G-CSF, use of G-CSF after cycle 1 of H/IDAC significantly reduced the rate of hospitalization for febrile neutropenia (p=0.039); however, no significant differences were noted for subsequent cycles. No significant differences were seen in duration of hospitalization, rate of documented infections, or time to treatment failure between groups. Overall survival was longer for patients who received G-CSF during their first cycle (p=0.018) and for those who received G-CSF during any of their cycles (p=0.04). Use of G-CSF prophylaxis after cycle 1 of H/IDAC consolidation for AML appears to reduce the frequency of hospitalization for febrile neutropenia and to increase overall survival compared with no G-CSF use. Prospective, controlled studies are needed to support our findings.

Effectiveness of Supportive Care Measurements to Reduce Infections During Induction for Children with Acute Myeloid Leukemia: A Report From the Children's Oncology Group

AbstractAbstract 1478▪▪This icon denotes a clinically relevant abstract Background:Current therapies for pediatric acute myeloid leukemia (AML) are intensive; infections are responsible for considerable morbidity and most non-relapse related mortality (NRM). Three supportive care strategies that have garnered much attention are prophylactic antibiotics, prophylactic granulocyte-colony stimulating factor (G-CSF) and hospitalization during profound neutropenia. The Children’s Oncology Group (COG) trial AAML0531 was a phase 3 study that included children with de novo AML treated with intensive chemotherapy, and randomized them to standard chemotherapy ± gemtuzumab ozogamicin. We surveyed participating COG sites mid-way through the trial to measure the effect of institutional standards for antibiotic prophylaxis, G-CSF prophylaxis, and discharge policy on Induction I infection risk and NRM for children on study. Methods:AAML0531 used 5 courses of intensive chemotherapy with Induction I consisting of cytarabine 100 mg/m2/dose intravenous (IV) every 12 h on days 1–10; daunorubicin 50 mg/m2/dose IV on days 1,3 and 5; and etoposide 100 mg/m2/dose IV on days 1–5 (ADE 10+3+5). Infections were collected prospectively and monitored in real-time to optimize reporting accuracy. In this analysis, infectious events were limited to Induction I to reduce the chance that a patient’s clinical course resulted in the patient receiving a supportive care practice different than the institutional standard. NRM was not limited to Induction I and NRM was defined as any induction death or deaths during intensification or within 30 days of being taken off study due to non-disease related causes. The survey included questions on institutional standards for antibacterial prophylaxis, antifungal prophylaxis, prophylactic G-CSF use and mandatory hospitalization until count recovery. Results:A total of 1024 patients were enrolled on AAML0531. The survey response rate from 216 COG sites was 180/216 (83.3%) and there were 897 non-Down syndrome patients treated at institutions responding to the survey. The use of any anti-bacterial prophylaxis was not associated with a reduction in sterile site bacterial infection and did not significantly alter the risk of Clostridium difficile or fungal infection. Penicillin or vancomycin prophylaxis was associated with an increased risk of any sterile site bacterial infection (odds ratio (OR) 1.96, 95% confidence interval (CI) 1.15 to 3.34; P=.014), Gram-negative infection specifically (OR 4.22, 95% CI 1.62 to 11.0; P=.003) and sterile site fungal infection (OR 3.67, 95% CI 1.31 to 10.3; P=.013). Anti-mold prophylaxis was associated with more sterile site bacterial infection (OR 1.87, 95% CI 1.06 to 3.29; P=.031) and a non-significant increase in Gram-negative infection (OR 2.95, 95% CI 0.97 to 8.95; P=.056). Anti-mold prophylaxis did not influence the rate of sterile site fungal infection. G-CSF prophylaxis and discharge policy did not impact on Induction I infections. None of these supportive care practices influenced NRM during induction or intensification. Conclusions:Penicillin or vancomycin prophylaxis was associated with more Gram-negative and fungal infections. These data do not support routine prophylaxis with these agents. Routine antibiotic prophylaxis, G-CSF prophylaxis, and discharge policy did not impact NRM. Disclosures:No relevant conflicts of interest to declare.

Patterns of Granulocyte Colony-Stimulating Factor (G-CSF) Use in Elderly Patients with Non-Hodgkin's Lymphoma (NHL) Receiving Myelosuppressive Chemotherapy

AbstractAbstract 5078 Background:Febrile neutropenia (FN) is a common and potentially serious complication of myelosuppressive chemotherapy in cancer patients. Oncology guidelines recommend primary G-CSF prophylaxis (PPG) in patients with a high risk of developing FN, which is risk > 20% based on myelotoxicity of the regimen itself or from a combination of the therapy, older age, comorbidities and disease characteristics (Lyman Cancer 2011, Crawford J Natl Compr Canc Netw 2011, Aapro Support Care Cancer 2010). There is a gap in the medical literature concerning current patterns of G-CSF use and FN occurrence among the elderly Medicare population receiving myelosuppressive chemotherapy for NHL. To correct this, we performed a retrospective analysis using a subset of the Medicare 5% database. Methods:The Medicare 5% claims data set (includes a representative 5% systematic sample of Medicare beneficiaries) was used to identify NHL patients age 65+ initiating chemotherapy between July 1, 2003 and June 30, 2009. Chemotherapy courses were identified for each patient; only the first course was used for this analysis. Using the National Comprehensive Cancer Network guidelines on Myeloid Growth Factors (NCCN V1. 2012), if they could be, chemotherapy course regimens were classified as high risk (HR, FN risk ≥ 20%) or intermediate risk (IR, FN risk ≥ 10% and < 20%) for FN. Up to 9 chemotherapy cycles were defined for the first course. Cycle one began on the first chemotherapy claim date and ended at the next chemotherapy claim occurring at least 20 days after the chemotherapy initiation; subsequent cycles were similarly defined. First administration of G-CSF [filgrastim (NEUPOGEN®) or pegfilgrastim (Neulasta®)] was classified as either PPG (within first 5 days of the beginning of the first cycle), secondary prophylaxis (within first 5 days of second or subsequent cycles), or reactive (day 6 or later of first or subsequent cycles). FN assessed during the chemotherapy course was defined as hospitalization with a code for neutropenia in any claim position. Results:We identified 1, 104 chemotherapy courses with high FN risk, the vast majority of which (1, 027) were R-CHOP. We also identified 77 courses with intermediate FN risk. Approximately sixty four percent of HR regimens and 77% of IR regimens were initiated without primary prophylaxis with growth factor. Daily filgrastim was used in 10% of PPG, and pegfilgrastim in 90%. Among HR courses, 22. 6% had ≥ 1 FN hospitalization and 5. 4% had ≥ 2; among IR courses 10% had 1 FN hospitalization. Conclusion:The use of prophylactic growth factor support is the recommended standard of care in elderly patients receiving R-CHOP (Repetto Eur J Cancer 2003). In this study the majority of elderly patients initiating R-CHOP chemotherapy did so without appropriate growth factor support which translated into a high incidence of FN hospitalizations (22. 1%).Chemotherapy regimen risk of FN (number of first cycles/courses)G-CSF use any time during the courseFirst G-CSF UseNo G-CSFAny G-CSFAny filgrastimAny pegfilgrastimBoth G-CSFsPrimary ProphylaxisSecondary ProphylaxisReactiveHR (n=1,104)26.7%73.3%21.6%62.0%10.4%36.1%18.1%19.1%R-CHOP (n=1,027)26.9%73.1%21.3%62.3%10.5%37.1%18.0%18.0%IR (n=77)41.6%58.4%18.2%50.6%10.4%23.4%14.2%20.8%HR regimens: R-CHOP (n=1027), HYPERCVAD+rituximab (33), RICE (20), ESHAP (12), Other (12).IR regimens: FM (67), GDP (5), Other (5). Disclosures:Page:Amgen Inc. : Employment, Equity Ownership. Chia:Amgen Inc. : Employment, Equity Ownership. Barron:Amgen Inc. : Employment, Equity Ownership. Choi:Amgen Inc. : Employment, Equity Ownership.

Non-Interventional Study Hexafil: G-CSF Use in Accordance to Guidelines?

AbstractAbstract 2057 Purpose of the study:Chemotherapy (CT) induced neutropenia (CIN) is a common complication in the treatment of cancer and often leads to modifications of antineoplastic treatment. Granulocyte-colony stimulating factors (G-CSF) are frequently used to prevent or treat CIN in cancer patients. The non-interventional observational study HEXAFIL on the use of biosimilar filgrastim (EP-2006) was conducted to provide further insight into its therapeutic efficacy and routine clinical use in Germany, especially in compliance with guidelines on the use of G-CSF (EORTC, ASCO). Methods:1460 patients who signed informed consents are to be enrolled at 100 German sites. Data is documented for up to 3 consecutive filgrastim-supported CT-cycles. Rates of modified CT-treatments (dose modification/discontinuation of drug) are calculated by the number and percentage of patients affected; data presented are based on the first CT-cycle. Inclusion/Exclusion criteria: www.germanctr.de. Results:By 7/2012, data of 955 patients were available. Patients' mean age was 59 years (19 to 89), 75% of them being female. Most common tumour entities were breast cancer (57.2%), NHL (10.7%), lung cancer (7.6%), ovarian cancer (4.0%) and Hodgkin lymphoma (3.1%). Substances most commonly used for chemotherapy were cyclophosphamide (50.7%), epirubicin (33.2%), docetaxel (23.6%), 5-fluorouracil (20.9%) and doxorubicin (15.6%). In line with published data only 1.9% of all patients experienced febrile neutropenia (FN), 8.7% neutropenic complications and 14% had leukopenia CTC 4 at nadir. As expected and according to guidelines the majority of patients received primary (39.3%, PP) or secondary prophylaxis (32.9%, SP) with biosimilar filgrastim, however, 25.8% were treated on demand (TX, i.e. after having experienced neutropenic complications in the first documented CT cycle or a drop in leukocytes putting the patient at acute risk of neutropenic complications). Interestingly, if viewed by the presence of baseline leukopenia, 76.9% of all patients without leukopenia (CTC 0) received G-CSF prophylaxis (PP/SP) but only 46.1% of all patients with leukopenia CTC 3/4. In patients without baseline leukopenia receiving filgrastim for PP, leukopenia CTC 3/4 at nadir was present in 32.9%, whereas in SP it was 50.6% and in TX 70.8%. Median filgrastim treatment duration was 4 d (1 to 14). Patients with PP received median 5 days of treatment starting on median day 6 after CT, whereas SP and TX patients were treated on median day 8 and 9, respectively, for a median duration of 3 days each. Accordingly, patients with neutropenic complications received treatment starting on median day 8 for 3 days (median), whereas patients without neutropenic complications started on median day 7 for 5 days (median); moreover, patients with FN only started biosimilar filgrastim therapy on median day 9. 93.9% of all documented patients received CT without any modification; in 4.6% of patients the dose of chemotherapy was modified and in 1.4% a chemotherapy drug was discontinued. Data indicate that patients with earlier and longer filgrastim treatment showed less chemotherapy disturbances, FN and neutropenic complications. Conclusions:Approximately 94% of all documented patients received filgrastim-supported CT-cycles without any modification of the CT-regimen. Yet, there is still room for improvement in prevention of CIN/FN in cancer patients as reflected by median start/treatment days and number of neutropenic complications. Moreover, daily injections should not impact the prophylactic use of G-CSF as revealed by self-assessment questionnaires in which patients reported handling of the needle guard system and of the pre-filled syringes to be easy or very easy (97.7% and 97.8%, respectively and calculated on questionnaires evaluable). Disclosures:Tesch:Amgen, Astra Zeneca, Boehring Ingelheim, Celgene, GSK, Hexal, Janssen Cilag, Lilly, Merck, Novartis, Pfizer, Roche: Honoraria; Amgen, Astra Zeneca, Boehring Ingelheim, Celgene, GSK, Hexal, Janssen Cilag, Lilly, Merck, Novartis, Pfizer, Roche; Sanofi Aventis: Consultancy. Abenhardt:Hexal: Honoraria. Dietze:Hexal: Honoraria. Chang:Hexal: Employment. Ottillinger:Hexal, Sandoz: Consultancy, Honoraria.

Primary prophylaxis with granulocyte colony-stimulating factor (GCSF) reduces the incidence of febrile neutropenia in patients with non-Hodgkin lymphoma (NHL) receiving CHOP chemotherapy treatment without adversely affecting their quality of life: cost–benefit and quality of life analysis

Treatment of non-Hodgkin lymphoma (NHL) with cyclophosphamide, vincristine, doxorubicin and prednisone (CHOP) is known to be associated with a significant risk of febrile neutropenia (FN) of up to 50% [Osby et al. 2003 Blood 101(10): 3840-3848; Lyman and Delgado 2003 Cancer 98(11): 2402-2409]. This study sought to examine the impact of primary granulocyte colony-stimulating factor (GCSF) prophylaxis on the incidence of FN, quality of life and overall cost. In this retrospective cohort study, a group of 65 consecutive patients who received CHOP chemotherapy for NHL between December 2006 and October 2009 was studied. Patients either received filgrastim (300 mcg, average of seven doses), pegylated filgrastim (6 mg, single dose), or no GCSF prophylaxis. In addition, 19 patients were asked to complete Functional Assessment of Cancer Therapy: General quality-of-life questionnaires. Overall, patients who received primary GCSF prophylaxis had significantly fewer FN compared to those who did not (5 vs. 60%, p < 0.0001; numbers needed to treat of 1.8; 95% confidence interval, 1.6-2.9). Cost-benefit analysis showed that the GCSF prophylaxis was associated with only a small increase in direct financial cost ($238 NZD [US$189] more to give primary GCSF prophylaxis per patient vs. no prophylaxis). The quality of life assessment showed that the patients' quality of life scores were similar to the published data from the validation study population (466 patients with mixed cancers) for Functional Assessment of Cancer Therapy. Our study shows that primary GCSF prophylaxis is effective in preventing FN in patients receiving CHOP chemotherapy for NHL without adversely affecting their quality of life, and is cost effective.

Phase I dose-escalation study of aflibercept in combination with docetaxel and cisplatin in patients with advanced solid tumours

Background:This phase I cohort study investigated aflibercept (vascular endothelial growth factor (VEGF) trap) plus docetaxel and cisplatin in patients with advanced solid tumours.Methods:Patients received intravenous aflibercept 4, 5, or 6 mg kg−1 with docetaxel and cisplatin (75 mg m−2 each) on day 1 of a 3-week cycle until progressive disease or unacceptable toxicity. Primary objectives were determining cycle 1 dose-limiting toxicities (DLTs) and the aflibercept recommended phase II trial dose (RP2D) for this combination.Results:During the dose-escalation phase (n=16), there were two DLTs of febrile neutropenia (at 4 and 5 mg kg−1). Granulocyte colony-stimulating factor prophylaxis was subsequently recommended. The RP2D of aflibercept was established at 6 mg kg−1 and administered to 14 additional patients. The most frequent grade 3/4 adverse events (AEs) were neutropenia (43.3%), stomatitis (20.0%), asthenia/fatigue (20.0%), and hypertension (16.7%). All-grade AEs associated with VEGF blockade included epistaxis (83.3%), dysphonia (70.0%), proteinuria (53.3%), and hypertension (50.0%). There were five partial responses (16.7%) and 18 cases of stable disease (60.0%) (lasting >3 months in 10 patients). There were no pharmacokinetic (PK) interactions between the three drugs.Conclusion:Aflibercept 6 mg kg−1 with docetaxel and cisplatin 75 mg m−2 every 3 weeks is the RP2D based on tolerability, antitumour activity, and PKs.

Review of practice patterns of primary granulocyte-colony stimulating factor prophylaxis and impact on febrile neutropenia rate and chemotherapy delivery in patients with early breast cancer treated with modern adjuvant chemotherapy.

e19541 Background: Febrile neutropenia (FN) is a major complication of chemotherapy and is associated with substantial morbidity and mortality. Primary prophylaxis with granulocyte colony-stimulating factors (PP-G-CSF) is recommended for regimens with FN risk above 20%. We undertook a review of practice patterns of PP-G-CSF and impact on febrile neutropenia rate and chemotherapy delivery in patients with early breast cancer (EBC) treated with modern adjuvant chemotherapy (ACT) at the Cancer Centre of Southeastern Ontario. Methods: Women with EBC receiving at least one cycle of modern ACT (taxane containing regimens with or without anthracyclines) between January 2009 and December 2011 were included in our review. We collected demographic, disease-related, treatment-related, and outcome variables for each patient. Results: 239 women were treated with modern ACT during the specified period and were included in our analysis. Median age was 55 (32-80); 197 (82%) were &lt;65 years and 148 (62%) were postmenopausal. 212 (89%) patients were treated with an anthracycline-taxane (A-T) regimen and 27 (11%) with a taxane (T) regimen. 145 patients (61%) received PP-G-CSF: 47 (32%) with filgrastim (F) and 98 (68%) with pegfilgrastim (PF). Of all patients 50 (21%) developed at least one FN episode. PP-G-CSF led to lower FN rate (15% vs 31%; p=0.002), reduced dose delay (17% vs 27%; p=0.060) and dose reduction (19% vs 25%; p=0.28) of planned ACT. In women receiving PP-G-CSF higher rate of FN was associated with age ≥ 65 years (27% vs 12% if &lt; 65 years; OR 2.8, p=0.053); T regimen (30% vs 12% for A-T; OR 3.1, p=0.041) and F use (28% [n=13] vs 8% [n=8] with PF; OR 4.3, p=0.003). Conclusions: In this single-centre retrospective cohort study patients with EBC treated with modern ACT had a high rate of FN (31%) without PP-G-CSF. More than half (61%) of the patients received PP-G-CSF which led to fewer FN episodes and increased delivery of planned ACT; however, the risk of FN remained high at 15%. Factors linked to higher rate of FN despite PP-G-CSF were older age, taxane-based chemotherapy and use of filgrastim.

The need for improved neutropenia risk assessment in DLBCL patients receiving R-CHOP-21: Findings from clinical practice

Febrile neutropenia (FN) risk-assessment and granulocyte-colony stimulating factor (G-CSF) prophylaxis use in clinical practice was evaluated in patients with diffuse large B-cell lymphoma receiving R-CHOP-21. More G-CSF primary prophylaxis was used in patients assessed as high FN risk, but R-CHOP-21 was associated with substantial myelotoxicity in both high- and low-risk groups. In a multivariate analysis, older age, poor performance status, lower baseline hemoglobin, and lack of G-CSF prophylaxis were significantly associated with occurrence of FN in any cycle. Results highlight the need for improved FN risk-assessment and thorough guideline adherence to further reduce FN and better support chemotherapy delivery.

Impact of renal impairment and granulocyte colony stimulating factor (GCSF) on bleomycin-induced pneumonitis (bleo lung), febrile neutropenia (FN), and survival in patients (pts) with germ cell tumor (GCT) treated with chemotherapy (chemo).

328 Background: Use of GCSF and the development of renal impairment in GCT pts receiving chemo are common, but their effect on toxicity and survival is unclear. This study examines the impact of GCSF and renal impairment on bleo lung, FN and survival, in GCT pts receiving 1st line chemo. Methods: Clinical data from our institutional GCT database was complemented by review of radiology, pharmacy and medical records. All GCT pts receiving 1st line chemo between 1-Jan-00 and 31-Dec-10 were included. Pts receiving at least one GCSF dose were identified. Renal impairment during chemo was defined as any serum creatinine above the institutional upper limit of normal. Bleo lung was graded (G1-5) using CTCAE criteria. FN was defined as temperature ≥38C and neutrophil count &lt;1.0. Results: The cohort consisted of 260 GCT pts, median age 31.5 years, 171 (66%) had IGCCCG good risk disease, 42 (16%) intermediate, and 41 (16%) poor, while 6 (2%) received adjuvant chemo. 159 (61%) received GCSF and 49 (19%) developed renal impairment. 212 (82%) received BEP of which 73 (34%) developed bleo lung (56 pts G1 asymptomatic, 13 pts G2, 4 pts ≥G3). Renal impairment was associated with bleo lung in univariate (OR 2.87, p=0.008) and multivariate (OR 2.69, p=0.01) analyses. GCSF was associated with increasing severity of bleo lung (OR 1.86, p=0.045) but this was not significant in a multivariate analysis (OR 1.72, p=0.08). FN occurred in 33 (13%) of 260 pts. Renal impairment (OR 3.91, p=0.001) was associated with FN. Primary GCSF prophylaxis reduced FN (OR 0.26, p=0.001), however, 8 (7%) of 112 patients developed FN in spite of GCSF prophylaxis. Survival analyses demonstrated GCSF and renal impairment did not impact progression free or overall survival (OS), however, bleo lung was associated with poorer OS in a multivariable Cox proportional hazards analysis (HR 2.85, p=0.029). Conclusions: Our findings demonstrate both renal impairment and GCSF are risk factors for bleo lung, while renal impairment itself is also a risk factor for FN. Additionally, we identify bleo lung as a significant poor prognostic factor for OS.

Evaluation of the role of UGT1A1 genotype testing in colorectal cancer patients administered irinotecan and the occurence of grade 3 and 4 neutropenia.

412 Background: Irinotecan is metabolized primarily in the liver by the carboxylesterase enzyme to the SN-38 active metabolite and is then inactivated through conjugation by the UGT1A1 enzyme, a polymorphic enzyme. Individuals genotyped with the homozygous allele have an increased risk for grade 3 and 4 neutropenia. Methods: A retrospective cohort analysis was conducted in the Kaiser Permanente California regions. The study period was November 1, 2005 to July 1, 2010 and included patients that were 18 years of age or older, newly initiated on irinotecan for colorectal cancer and had no previous irinotecan therapy within six months of the initiation dose. Patients were excluded if they were enrolled in clinical trials, on granulocyte-colony stimulating factor prophylaxis, and genotype tested for UGT1A1 and subsequently not treated with irinotecan. Patients tested with the UGT1A1 assay were grouped according to their genotype results: wild-type, heterozygous, or homozygous*28. The incidence of grade 3 and 4 neutropenia were compared among patients tested for UGT1A1 variant alleles by their genotype results. Results: A total of 305 (28%) patients were tested with the UGT1A1 assay with a mean age of 62 (+/- 12) years, and 52% of the population female. There were 161 (53%) wild-type, 123 (40%) heterozygous, and 21 (7%) homozygous patients. The median irinotecan dose was 150 mg/m2 (124-180 mg/m2) and median number of irinotecan cycles were 6 (3-12). The wild-type, heterozygous, homozygous*28 population had a 21% (33/161), 24% (29/123), and 48% (10/21) rate of grade 3 and 4 neutropenia. When the homozygous*28 group was compared to the heterozygous and wild-type genotype the adjusted Cox Proportional Hazard was 3.05 (95% CI, 1.55-5.99), p = 0.001. The Kaplan-Meier Log Rank Test yielded a p-value of 0.002. Conclusions: The adjusted risk for homozygous genotyped patients was three times higher compared to the wild-type and heterozygous group for grade 3 and 4 neutropenia. Additional investigational studies examining the benefits of UGT1A1 genotyping as a prognostic test and further effect of dosage adjustments in UGT1A1*28 homozygous initiated on irinotecan therapy are needed.