Primary Prophylactic Granulocyte Colony-stimulating Factor Research Articles

Patient characteristics associated with primary prophylactic granulocyte colony-stimulating factor (G-CSF) use among women treated for early-stage breast cancer.

e12605 Background: The National Comprehensive Cancer Network (NCCN) recommends several chemotherapy regimens for early-stage breast cancer that have elevated risk of neutropenia (>20%). In these regimens, primary prophylactic use of granulocyte colony-stimulating factor (G-CSF) is recommended. Little is known about how patient-level factors relate to receipt of prophylactic G-CSF among women receiving these regimens. Methods: In the Optimal Breast Cancer Chemotherapy Dosing (OBCD) Study, we examined use of G-CSF among women with stage I-IIIA breast cancer between 2005-2019 in Kaiser Permanente Northern California (KPNC) and Kaiser Permanente Washington (KPWA). We evaluated the patient-level factors associated with primary prophylactic G-CSF use (≤7 days before to ≤3 days after first day of chemotherapy) among women receiving chemotherapy regimens with high risk of neutropenia, for which the NCCN guidelines recommend prophylactic G-CSF use. Multivariable-adjusted prevalence ratios (PR) and their corresponding 95% Confidence Intervals (95% CI) were calculated using generalized linear models of the Poisson family with a log link-function and robust standard errors. Results: Overall, while all 3,083 women receiving these regimens ultimately received G-CSF, 2412 (79%) received primary prophylactic G-CSF within the period 7 days prior to 3 days post first cycle. Younger women had higher prevalence of prophylactic G-CSF receipt (82.7% in ages 18-39 years vs. 58.1% in 70+ years). Black women had higher prevalence of receipt compared to white women (82.7% in non-Hispanic Black women vs 76.1% in White women). Women with a higher body mass index (BMI) had lower prevalence of receipt compared to normal weight women (73.3% in 35+ kg/m2 group vs 81.5% in 18.5-<25 kg/m2 group). In multivariable models, older women were less likely to receive prophylactic G-CSF (PR70+ vs 18-39: 0.69; 95% CI: 0.57-0.84; p-trend<0.001), as were those with a higher BMI (PRBMI 35+ vs 18.5-<25: 0.92; 95% CI: 0.85, 0.97; p-trend=0.006), and a later year of diagnosis (PR2016-19 vs 2005-07: 0.81; 95% CI: 0.77, 0.85; p-trend<0.001). Although race/ethnicity was not significantly associated with receipt of prophylactic G-CSF use overall in multivariable models, we observed Non-Hispanic Black women to experience slightly higher likelihood of G-CSF receipt than Non-Hispanic White women (PR: 1.08; 95% CI: 1.02, 1.15). Conclusions: Women of older age and those with higher BMI were less likely to receive primary prophylactic G-CSF, as were women treated in later years. Further research looking at timing of G-CSF use is warranted, as are studies examining provider/facility-level factors in relation to patterns of G-CSF use, G-CSF’s impact on survival outcomes, and the real-world impact of decisions around G-CSF use across age, BMI, and racial/ethnic groups.

Abstract PO5-16-11: Novel antibody-drug-conjugates in clinical routine: adherence, efficacy and tolerability - real-world data from German breast centers

Abstract The third-generation antibody-drug conjugates, Trastuzumab-Deruxtecan (T-DXd) and Sacituzumab Govitecan (SG), have been approved for the treatment of metastatic breast carcinoma in various subtypes and therapeutic settings based on compelling Phase III study data. (DESTINY-Breast03 (T-DXd; HER2-positive), DESTINY-Breast04 (T-DXd; HER2-low), ASCENT (SG; triple-negative), and TROPiCS-02 (SG; HR+/HER2-negative). The aim of this retrospective study conducted at two major German Breast centers was to evaluate the tolerability, adherence, and efficacy of both substances in the real-world setting. All patients treated outside of clinical trials with T-DXd or SG at the Department of Gynecology and Obstetrics, Ulm University Hospital and the Department of Women’s Health, Tuebingen University Hospital between November 2020 and May 2023 were included in this retrospective analysis. Seventy-five patients were included [T-DXd: 46; SG: 29]. The mean duration of therapy was 5.4 months [T-DXd: 6.2; SG: 4.2]. The real-world cohort was more heavily pretreated than the corresponding study cohorts, with a mean of 4.2 systemic therapies in the metastatic setting prior to T-DXd therapy and 3.6 systemic therapies prior to SG therapy. The administered cumulative dose on average was 87.9% [T-DXd: 94%; SG: 79%] of the theoretical full dose or 95.3% [T-DXd: 98%; SG: 92%] when considering dose reductions that occurred. Hematotoxicities of CTC ≥ 3° occurred in 11% of patients treated with T-DXd and in 41% of patients treated with SG. Neutropenia was the predominant severe hematotoxicity (CTC≥III°) observed during SG therapy, occurring in 38% of patients. The occurrence of neutropenia during SG therapy was reduced with primary prophylactic administration of Granulocyte-Colony Stimulating Factor (GCSF), with a rate of 29% (21/29) of patients experiencing neutropenia ≥CTC-III°, compared to 63% (8/29) without primary prophylactic GCSF. Therapy-associated pneumonitis under T-DXd occurred in 5 out of the 46 included patients and was successfully treated with corticosteroids in all cases (CTC II° in 4 cases, CTC III° in 1 case). The median progression-free survival (PFS) from initial administration was 7.7 months under T-DXd [HER2-positive: 9.0; HER2-low: 6.1], and 4.8 months under SG [TNBC 4.8; HR+/HER2-negative: 2.8]. The median overall survival from initial administration was 27.1 months under T-DXd [HER2-positive: 27.1; HER2-low: not reached], and 11.9 months under SG therapy [TNBC: 11.0, HR+/HER2-negative: not reached]. This analysis provides evidence of the efficacy and tolerability of T-DXd and SG in a heterogeneous and heavily pretreated cohort in a real-world setting. However, a conclusive assessment of progression-free survival (PFS) and overall survival (OS) is not feasible yet, as a substantial number of patients are still under treatment. Updated PFS and OS data, with a specific focus on the therapy indication, will be presented at the meeting. Citation Format: Henning Schäffler, Dominik Dannehl, Kristina Veselinovic, Franziska Mergel, Kerstin Pfister, Brigitte Rack, Visnja Fink, Elena Leinert, Lea Volmer, Tobias Engler, Sara Brucker, Wolfgang Janni, Andreas Hartkopf. Novel antibody-drug-conjugates in clinical routine: adherence, efficacy and tolerability - real-world data from German breast centers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-16-11.

Abstract PO1-12-06: Is it appropriate to select patients for primary prophylactic use of pegfilgrastim based on the risk of febrile neutropenia?

Abstract Background: Febrile neutropenia (FN), a major hematologic adverse event in perioperative chemotherapy for breast cancer, is more prevalent among Asians than in Caucasian populations. Four main guidelines, i.e., ASCO, EORTC, NCCN, and ESMO, provide recommendations regarding the appropriate use of hematopoietic growth factors. These guidelines recommend primary prophylaxis with granulocyte colony-stimulating factor (G-CSF) based on the estimated incidence of FN, primarily defined by the chemotherapy regimen. G-CSF administration is recommended when the incidence of FN is ≥20% or 10–20% with risk(s). However, the incidence of FN varies depending on the trial and design, and patient-specific risk factors for FN remain unclear. We previously performed a multicenter prospective cohort study in Japan, the CSPOR-BC FN study, evaluating the incidence of FN during perioperative chemotherapy for breast cancer. Herein, we conducted an additional analysis to explore thresholds of patient-specific risk factors for FN that could be evaluated before chemotherapy. We analyzed the risk factors for FN and verified the appropriateness of patient selection for prophylactic G-CSF administration. Methods: The previously reported CSPOR-BC FN study (PubMed ID=33631458) consecutively enrolled 1005 patients with stage I–III breast cancer between August 2015 and July 2017. In the current additional analysis, we intended to have 477 patients in the visiting group that evaluated true-FN, defined as ≥37.5℃ and grade 4 neutropenia. Multivariate analysis of risk factors for FN was performed, followed by the determination of cutoff values for age and pretreatment absolute neutrophil count (ANC) as risk factors. Results: Chemotherapy regimens administered were FEC (fluorouracil, epirubicin, and cyclophosphamide) in 170 patients (36%), E(A)C (epirubicin (doxorubicin) + cyclophosphamide) in 165 patients (35%), and TC (docetaxel + cyclophosphamide) in 142 patients (30%). The incidence of FN was 28.7% (N = 137). To evaluate the risk factors for FN, we predefined regimens, age, performance status (PS), stage, chemotherapy or radiotherapy history, infectious wounds, open wounds, ANC, and renal and liver dysfunction as potential risk factors. Multivariate analysis of risk factors for FN identified regimen (TC), age (≥65), low pretreatment ANC, treatment setting, and no primary pegfilgrastim prophylaxis as significant risk factors. Two patient-specific risk factors (age and pretreatment ANC) were analyzed. Logistic regression analysis revealed that age≥65 years was a significant risk factor (odds ratio=2.24, 95% confidence interval: 1.34–3.75). Applying a cutoff of 65 years (age) to predict FN, the sensitivity and specificity were 28.4 and 83.8%, respectively, which were inaccurate. Despite applying a cutoff of 67 years optimized from the receiver operating characteristic (ROC) curve, the sensitivity (22.4%), specificity (90.7%), and area under the curve (0.519) indicated low discrimination for predicting FN. The incidence of FN by age group was as follows: < 45 years, 30.8%; 45–55 years, 26.4%; 55–64 years, 20.9%; ≥65 years, 39.6%. Additionally, applying a cutoff of 2436/µL (pretreatment ANC) optimized from the ROC curve, the observed sensitivity (27.6%) and specificity (83.8%), and area under the curve (0.558) also indicated low discrimination for predicting FN. The incidence of FN by stratum of pretreatment ANC was as follows: < 2000, 33.3%; 2000–3000, 30.7%; 3000–4000, 29.9%; and >4000, 24.6. Accordingly, setting a cutoff value to predict FN incidence using age and/or pretreatment ANC was deemed inappropriate. Conclusion: Selecting patients for primary prophylactic G-CSF based on the existing FN risk can be challenging. Primary prophylactic G-CSF would be considered for every patient undergoing perioperative chemotherapy for breast cancer, especially Asians. ROC curve for FN and age. The AUC was 0.519. ROC curve for FN and neutrophil count. The AUC was 0.558. Citation Format: Kazutaka Narui, Takashi Ishikawa, Ikumi Takashima, Kosuke Kashiwabara, Yukari Uemura, Yuichiro Kikawa, Naruto Taira, Hirofumi Mukai. Is it appropriate to select patients for primary prophylactic use of pegfilgrastim based on the risk of febrile neutropenia? [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-12-06.

Febrile neutropenia incidence and the variable toxicity profile between brand and generic docetaxel in the adjuvant treatment of breast cancer with docetaxel and cyclophosphamide regimen.

To assess the incidence of febrile neutropenia without primary granulocyte colony-stimulating factor prophylaxis in patients undergoing chemotherapy with adjuvant docetaxel and cyclophosphamide, and to evaluate the toxicity profile of brand-name docetaxel (Taxotere ® ) and the generic formulation. This retrospective study was conducted using data obtained from electronic medical records of patients treated at a Brazilian cancer center. Patients with breast cancer who underwent adjuvant treatment between January 2016 and June 2019 were selected. Data were analyzed using chi-square and Fisher correlation of variables, and multivariate analyses were adjusted for propensity score. A total of 231 patients with a mean age of 55.9 years at the time of treatment were included in the study. The majority (93.9%) had luminal histology, 84.8% were at clinical stage I, and 98.2% had a good performance status. The overall incidence of febrile neutropenia in the study population was 13.4% (31 cases). The use of brand-name docetaxel (Taxotere ® ) was the only factor associated with febrile neutropenia occurrence (OR= 3.55, 95%CI= 1.58-7.94, p=0.002). In patients with breast cancer who require treatment with adjuvant docetaxel and cyclophosphamide regimen, the toxicity profile differs between brand-name and generic docetaxel. Regardless of the formulation used, the incidence of febrile neutropenia was less than 20%, which may allow for the omission of primary prophylactic granulocyte colony-stimulating factor use in this setting.

A retrospective review of primary prophylaxis with granulocyte-colony stimulating factor (G-CSF) for patients with genitourinary malignancies receiving chemotherapy during the COVID-19 pandemic and implications for the future.

115 Background: To mitigate the risks of chemotherapy associated neutropenia, during the COVID-19 pandemic, all genitourinary (GU) cancer patients treated with chemotherapy at the Princess Margaret Cancer Centre (PMCC) were offered primary prophylaxis with GCSF. We hypothesize that this reduced rates of febrile neutropenia, hospitalizations, healthcare costs and improved overall outcomes, compared to GU cancer patients treated with chemotherapy without GCSF in the 2 years prior to the pandemic. Methods: We performed a retrospective review of GU cancer patients, receiving curative or palliative intent chemotherapy, with or without primary GCSF prophylaxis between January 2018 and June 2022. GCSF was given either as a single dose or as consecutive doses post chemotherapy. Main outcomes were incidence of febrile neutropenia, hospitalization, health care expenditures as well as disease specific outcomes. Results: Overall, 248 patients with prostate cancer (44%), urothelial cancers (33%) germ cell (21%), and rare GU cancers (4%) were identified. Median age was 70 (range 19-91), 92% were male, 65% were ECOG 0/1. Treatment intent was neoadjuvant (13%), adjuvant (20%), or palliative (67%). Main regimens used were docetaxel, cabazitaxel, carboplatin, cisplatin/etoposide, gemcitabine/cisplatin and BEP. Median follow-up was 10.5 months (0.23-52.3 months). A total of 206/248 received primary GCSF prophylaxis. During chemotherapy, the median white blood cell levels were higher in the GCSF group compared to the non-GCSF group (14.1*10*9/L vs 2.90*10*9/L, p<0.0001); and neutropenia rates were markedly lower (2% vs. 93%, P=<0.0001). Hospital admission rates were significantly lower in G-CSF users compared to non-users (19% vs. 69%, P<0.0001). Symptomatic disease progression 13% was the leading cause of admission in the G-CSF group. Infectious causes such as UTI, pneumonia, COVID-19, and sepsis were seen in only 12% of the G-CSF group compared to 31% in the non-users. G-CSF was generally well tolerated with just 0.97% discontinuing G-CSF. Conclusions: During the COVID-19 pandemic, primary prophylactic G-CSF use in GU cancer patients, undergoing chemotherapy significantly lowered rates of both febrile neutropenia and hospitalizations and could be a cost-effective strategy in this patient population that warrants further study.

Patterns of primary prophylactic granulocyte colony-stimulating factor use in older Medicare patients with cancer receiving myelosuppressive chemotherapy.

Guidelines recommend primary prophylactic (PP) granulocyte colony stimulating factor (G-CSF) for prevention of febrile neutropenia (FN) in patients receiving myelosuppressive chemotherapy with high risk (HR: > 20%), or intermediate risk (IR:10-20%) of FN and ≥ 1 patient risk factor (e.g., age ≥ 65y). The current retrospective cohort study describes patterns of PP-G-CSF in older Medicare patients undergoing myelosuppressive chemotherapy with HR/IR of FN. Patients aged ≥ 66y initiating chemotherapy regimens with HR/IR of FN to treat breast, colorectal, lung, or ovarian cancer, or Non-Hodgkin's Lymphoma were selected using Medicare 20% sample (2013-2015) and 100% cancer patient (2014-2017) data. PP-G-CSF use was identified in the first cycle. Timing of pegfilgrastim pre-filled syringe (PFS) administration, proportion of patients completing all cycles (adherence) with pegfilgrastim PFS or on-body injector (OBI), and duration of short-acting G-CSF (sG-CSF) was described across all cycles. Of 64,893 patients receiving HR/IR for FN, 71% received HR and 29% IR regimens. Overall, PP-G-CSF use in the first cycle was 53% (HR: 74%; IR: 44%) and varied across cancers. Adherence with pegfilgrastim was slightly higher among OBI initiators (78%) than PFS (74%). Number of PP-sG-CSF administrations (mean [SD]) per cycle was 5.1 (SD: 2.7) overall, 5.4 (2.6) for HR, and 4.9 (2.7) for IR. Despite cancer treatment guidelines recommending PP-G-CSF use to reduce risk of FN associated with HR and IR (with ≥ 1 patient risk-factor) regimens, PP-G-CSF remains underutilized in older patients, across cancer types and regimens. Opportunities exist for improvement in use of PP-G-CSF.

Underutilisation of prophylactic G-CSF in breast cancer patients receiving adjuvant docetaxel/cyclophosphamide chemotherapy

Docetaxel/cyclophosphamide (TC) is a widely used adjuvant chemotherapy regimen, especially in patients with node-negative or low-risk node-positive breast cancer. Guidelines recommend the use of prophylactic granulocyte colony-stimulating factor (G-CSF) to prevent febrile neutropenia. In this study, we aimed to explore the use of G-CSF as a primary prophylactic and determine the factors influencing its use. This retrospective study used nationwide claims data from the National Inpatient Sample compiled by the Health Insurance Review and Assessment Service in South Korea from 2018. The claims data included 10% of inpatients admitted at least once in 2018 and 1% of outpatients who were not admitted. Female patients with breast cancer who received an adjuvant TC regimen after surgery were selected. Primary prophylactic G-CSF was defined as G-CSF prescribed within two days of the first cycle of TC. The factors influencing its utilisation were investigated using the chi-square test and a multiple logistic regression model. A total of 229 patients were included in the analysis. The proportion of patients who received primary prophylactic G-CSF treatment after the first cycle of TC was 55.5%. The factors positively influencing G-CSF utilization were patients’ age ≥65 years, location (i.e. metropolitan areas), and the type of healthcare facility (i.e. non-tertiary hospitals). The use of prophylactic G-CSF in patients with breast cancer who received the adjuvant TC regimen was insufficient. The use of primary G-CSF prophylaxis should be emphasised to reduce the risk of febrile neutropenia among patients receiving a myelosuppressive TC regimen.

Association of primary prophylactic (PP) granulocyte-colony stimulating factor (G-CSF) use with chemotherapy dose modifications and relative dose intensity (RDI) among breast cancer patients receiving high-risk regimens for febrile neutropenia (FN).

314 Background: FN is a primary driver of chemotherapy modification and reduced RDI. Breast cancer patients often receive regimens with high risk ( > 20%) for FN. PP G-CSF use is recommended to decrease incidence of infection, as manifested by FN. Real-world evidence describing the association of G-CSF with reduced RDI in breast cancer patients is lacking. Methods: We retrospectively analyzed Flatiron Health Electronic Health Record data from 2011 to 2019 of adult female breast cancer patients initiating high-risk for FN chemotherapy regimens. PP G-CSF (pegfilgrastim, filgrastim, or biosimilars) use was assessed in the first and subsequent cycles of chemotherapy overall and by modality (on-body injector [OBI] vs. pre-filled syringe [PFS]). Standard dose was defined by NCCN guidelines. RDI was defined with respect to dose and timing of delivery: (delivered dose intensity/standard dose intensity)*100 and categorized as < 85% vs ≥85%. Characteristics were described by G-CSF use and adjusted relative risks (ARRs) were estimated for the association between G-CSF use and RDI, adjusting for age, serum hemoglobin, ECOG, HER2 status, and HR status. Results: There were 27,812 breast cancer patients included with a median age of 57 years. Most (90%) received PP-G-CSF. Four cycles of TC (docetaxel + cyclophosphamide) was the most common regimen prescribed (36%) and 82% of these patients received PP-G-CSF support in the first cycle, with OBI given more often than PFS (62% vs 38%). Second most common was dd AC-T Q1W (doxorubicin + cyclophosphamide followed by paclitaxel) and 98% of these patients received PP G-CSF (59% OBI vs 41% PFS). 80% of G-CSF users (vs 48% of those with no G-CSF) completed 4 or more cycles of chemotherapy (all regimens had ≥4 planned cycles). G-CSF users had a significant reduction in risk of RDI < 85% in Cycle 1 (ARR: 0.60; 95% confidence interval [CI]: 0.43 – 0.85) and Cycle 2 (ARR: 0.76; 95% CI: 0.59 – 0.97). At the overall chemotherapy course level, the risk of RDI < 85% was not significantly different by G-CSF use (ARR: 0.83; 95% CI: 0.63 - 1.08). There was no significant difference in risk of reduced RDI between OBI and PFS (ARR: 1.13; 95% CI: 0.94 - 1.35). Conclusions: This study revealed that 90% of breast cancer patients receiving high-risk for FN chemotherapy received PP-G-CSF support and completed more cycles than those who did not receive G-CSF. G-CSF users had lower risk of a reduced RDI in Cycles 1 and 2.

Systematic review and meta-analysis of febrile neutropenia risk with TCH(P) in HER2-positive breast cancer.

Docetaxel, carboplatin and trastuzumab, with or without pertuzumab (TCH(P)), has become the preferred (neo)adjuvant regimen for HER2-positive breast cancer. However, its associated febrile neutropenia (FN) risk is unclear: pivotal studies reported FN risks < 10%, but in clinical practice, a high FN rate (> 20%) was observed. This systematic review and meta-analysis determine the FN risk associated with TCH(P) and the indication for primary prophylactic granulocyte colony-stimulating factor (PP G-CSF). The MEDLINE, Embase, Web of Science and Cochrane databases were searched for full-text English articles reporting the FN incidence in early breast cancer patients receiving (neo)adjuvant TCH(P). The primary endpoint was the pooled crude FN incidence in patients treated without PP G-CSF using the random effects method. Secondary endpoints were the FN risk with PP G-CSF support, age-related differences in FN and differences in risk with TCH versus TCHP. Seventeen studies were included in the systematic review. The pooled estimates of FN incidences were 27.6% (95% CI 18.6 to 37.1) in patients who did not receive PP G-CSF (primary meta-analysis, 9 studies, n = 889) versus 5.0% (95% CI 2.6 to 8.0) in patients administered PP G-CSF (secondary meta-analysis, 7 studies, n = 445). Two studies reported non-significant age-related differences in FN. The risk comparison between TCH and TCHP was inconclusive. The crude FN risk associated with (neo)adjuvant TCH(P) is over 20%, the upper limit above which the international guidelines unanimously advise PP G-CSF administration. G-CSF prophylaxis effectively reduces FN risk and should become the standard of care with (neo)adjuvant TCH(P).

Febrile neutropenia and role of prophylactic granulocyte colony-stimulating factor in docetaxel and cyclophosphamide chemotherapy for breast cancer

Febrile neutropenia (FN) incidence during docetaxel and cyclophosphamide (TC) chemotherapy, known as a high-risk regimen, differs among countries. The role of prophylactic granulocyte colony-stimulating factor (G-CSF) in FN is unclear. This study aimed to investigate FN frequency and relative dose intensity (RDI) of TC chemotherapy in patients with breast cancer and identify the correct population requiring prophylactic G-CSF. In total, 205 patients with breast cancer were scheduled for TC chemotherapy (docetaxel/cyclophosphamide 75/600 mg/m2, every 3 weeks, 4 cycles) as adjuvant chemotherapy. Trastuzumab (8 mg/kg; continued with 6 mg/kg) was administrated intravenously for human epidermal growth factor receptor 2 (HER2)-positive cancer. Fifty-five patients received primary prophylactic measures (G-CSF: 20 and antibiotics: 35). We investigated the frequency of FN and hospitalization, RDI, and the factors related to FN, adverse events, hospitalization, and RDI. FN occurred in 70 patients (35.7%). FN incidence was noted in 41.1% without any prophylactic measures and in 5.0% with prophylactic G-CSF. In multivariate analysis, the independent risk factors of FN were older age (≥ 60 years, P = 0.017) and without primary prophylactic G-CSF (P = 0.011). Eleven patients (5.6%) were hospitalized of which 8 (72.7%) were elderly. The median RDIs of docetaxel and cyclophosphamide were 96.7% and 99.7%, respectively. FN frequency during TC chemotherapy was high, and primary prophylactic G-CSF reduced FN incidence. Primary prophylactic G-CSF is an effective therapy for preventing FN during TC chemotherapy. However, prophylactic G-CSF should be considered for elderly patients based on the low hospitalization rate and the high RDI.

Is high‐risk neuroblastoma induction chemotherapy possible without G‐CSF? A pilot study of safety and treatment delays in the absence of primary prophylactic hematopoietic growth factors

Standard supportive care during induction therapy for high-risk neuroblastoma (HR-NBL) includes primary prophylactic granulocyte colony-stimulating factor (G-CSF) aimed at limiting duration of neutropenia, reducing infection risk, and minimizing treatment delays. Preclinical models suggest that G-CSF promotes maintenance of neuroblastoma cancer stem cells and may reduce the efficacy of chemotherapy. This study's objective was to determine the safety and feasibility of administering induction chemotherapy without routine use of prophylactic G-CSF. Children with newly diagnosed HR-NBL received six-cycle induction chemotherapy regimen without prophylactic G-CSF in four cycles. G-CSF was administered for stem cell mobilization after cycle 3 and granulocyte-monocyte colony-stimulating factor after cycle 5 prior to surgical resection of primary disease. The primary outcome measure was the incidence of grade 3 or higher infection. We hypothesized that the per patient infection rate would be comparable to our institutional baseline rate of 58% in patients with HR-NBL receiving induction chemotherapy with prophylactic growth factor support. The trial used an A'Hern single-stage design. Twelve patients with HR-NBL received 58 cycles of chemotherapy on study. Three patients completed the entire six-cycle regimen with no infections. Nine patients experienced grade 3 infections (bacteremia four, urinary tract infection two, skin/soft tissue infection three). No patients experienced grade 4 infections or required intensive care treatment for infection. A greater than expected number of serious bacterial infections were observed during administration of induction chemotherapy for HR-NBL without primary prophylactic G-CSF. These results support continued prophylactic administration growth factor during induction chemotherapy.

A Closed-loop Audit of 5 versus 10 Days of Primary GCSF Prophylaxis to Reduce the Incidence of Febrile Neutropenia in Early Breast Cancer Treatment

Purpose: Current guidelines recommend that patients with early breast cancer receiving chemotherapy that confers >20% risk of febrile neutropenia should have primary prophylactic granulocyte colony-stimulating factor (GCSF) on days 2–6 of chemotherapy [1,2]. An initial audit [3] demonstrated non-inferiority of 5 days versus 10 days of primary prophylactic GCSF in respect of febrile neutropenia rates seen in early breast cancer chemotherapy. Since 1 August 2016, our centre has switched from 10 days of prophylactic GCSF to 5 days. We re-audited febrile neutropenia rates following our change in practice.

Primary prophylactic granulocyte colony-stimulating factor according to ASCO guidelines has no preventive effect on febrile neutropenia in patients treated with docetaxel, cisplatin, and 5-fluorouracil chemotherapy.

The efficacy of primary prophylactic granulocyte colony-stimulating factor (G-CSF) in preventing febrile neutropenia (FN) in patients treated with docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy remains controversial. We compared the incidence of FN in patients treated with and without primary prophylactic G-CSF. We performed a retrospective analysis of 142 patients with locally advanced head and neck or esophageal cancer treated with TPF between January 2009 and March 2017. Among them, 116 patients started TPF without primary prophylactic G-CSF (control group) while 26 patients were given primary prophylactic G-CSF from day 7 of the first cycle of TPF (prophylactic group). The incidence of grade 4 neutropenia during the first cycle of TPF was significantly higher in the control group than in the prophylactic group [58.6% (n = 68) vs. 30.8% (n = 8), p = 0.02]. However, the incidence of FN in the first cycle was not significantly different between the two groups [32 patients (27.5%) in the control group and 8 patients (30.8%) in the prophylactic group (p = 0.62)]. In addition, the mean relative dose intensity throughout all cycles of TPF, as well as the survival time and response after TPF, were also not significantly different between the two groups. Primary prophylactic G-CSF from day 7 of the first cycle of TPF did not reduce the incidence of FN. Our findings suggest that the timing of primary prophylactic G-CSF, as recommended by the American Society of Clinical Oncology guidelines, should be modified to reduce the incidence of FN in TPF.

Efficacy of primary prophylactic GCSF in patients receiving docetaxel based chemotherapy for breast cancer.

e12516Background: Primary prophylactic Granulocyte Colony Stimulating Factor (PP-GCSF) is recommended for patients receiving single agent docetaxel (SAD) and docetaxel combination regimens (DCR) to...

74P - Febrile neutropenia and primary prophylactics in docetaxel plus cyclophosphamide chemotherapy for breast cancer: A Japanese institution experience

Background: Incidence of febrile neutropenia (FN) caused by docetaxel/cyclophosphamide (TC) therapy varies widely from country to country (5% at US Oncology research trial and 68.8% at Japanese trial), and the high hematotoxicity observed in Japanese patients may reduce relative dose intensity (RDI). Methods: Between April 2009 and June 2017, 205 patients with breast cancer received TC therapy (75/600 mg/m2, every 3 weeks, 4 cycles). We investigated the incidence of FN and RDI of TC therapy and the factors related to FN and low RDI. Results: The median patient age was 53 years. Fifty-five patients received primary prophylactics (20 granulocyte-colony stimulating factor (G-CSF) and 35 antibiotics). Excluding 9 patients with allergic reaction, FN occurred in 68 patients (34.7%). Among patients with primary prophylactic G-CSF, only one developed FN, whereas FN occurred in all the 11 patients with prophylactic antibiotics. Hospitalization was required in 6.3% of patients. In multivariate analysis, the independent risk factors of FN were older age (≥60 years, p = 0.017) and without primary prophylactic G-CSF (p = 0.011). The median RDIs of docetaxel and cyclophosphamide were 96.7% and 99.7%, respectively. Low RDI (<85%) was related to older age (p < 0.001), but not to primary prophylactics (G-CSF p = 0.247 and antibiotics p = 0.862).Table: 74PPredictors of FN incidenceFactorsUnivariate analysisMultivariate analysisOdds ratio (95% CI)POdds ratio (95% CI)PAge ≥60y5.16 (2.32-11.50)<0.0012.19 (1.15-4.17)0.017Hepatic dysfunction1.85 (0.40-8.62)0.4402.39 (0.56-10.10)0.237Renal dysfunction0.28 (0.06-1.38)0.1200.82 (0.29-2.30)0.708Prophylactic G-CSF0.39 (0.08-1.92)0.2500.07 (0.01-0.54)0.011Prophylactic antibiotics1.08 (0.43-2.72)0.8600.59 (0.26-1.34)0.206 Open table in a new tab Conclusions: Even though the FN incidence of TC therapy was over 20%, low hospitalization rate and high RDI were achieved in Japanese patients. Primary prophylactic G-CSF was useful to reduce FN of TC therapy for breast cancer, especially in older patients. Legal entity responsible for the study: Hiroshima University Funding: None Disclosure: All authors have declared no conflicts of interest.

A phase I dose-escalation study of selumetinib in combination with docetaxel or dacarbazine in patients with advanced solid tumors

BackgroundThe RAS/RAF/MEK/ERK pathway is constitutively activated in many cancers. Selumetinib (AZD6244, ARRY-142886) is an oral, potent and highly selective, allosteric MEK1/2 inhibitor with a short half-life that has shown clinical activity as monotherapy in phase I and II studies of advanced cancer. Preclinical data suggest that selumetinib may enhance the activity of chemotherapeutic agents. We assessed the safety, tolerability, and pharmacokinetics (PK) of selumetinib (AZD6244, ARRY-142886) in combination with docetaxel or dacarbazine in patients with advanced solid tumors.MethodsThis study was a phase I, open-label, multicenter study in patients aged ≥18 years with advanced solid tumors who were candidates for docetaxel or dacarbazine treatment. Part A of the study (dose escalation) evaluated safety, tolerability, PK, and maximum tolerated dose (MTD) of selumetinib twice daily (BID) with docetaxel 75 mg/m2 or dacarbazine 1000 mg/m2 administered every 21 days. Patients receiving docetaxel could be administered primary prophylactic granulocyte-colony stimulating factor according to standard guidelines. Part B of the study (dose expansion) further evaluated safety, tolerability, and PK in 12 additional patients at the MTD combinations determined in part A.ResultsA total of 35 patients received selumetinib plus docetaxel, and 25 received selumetinib plus dacarbazine. The MTD of selumetinib was 75 mg BID in combination with either docetaxel (two dose-limiting toxicity [DLT] events: neutropenia with fever, and thrombocytopenia) or dacarbazine (one DLT event: thrombocytopenia). Common adverse events occurring with each treatment combination were diarrhea, peripheral/periorbital edema, fatigue, and nausea. PK parameters for selumetinib and docetaxel or dacarbazine were similar when administered alone or in combination. Partial responses were reported in 6/35 patients receiving selumetinib plus docetaxel and 4/25 patients receiving selumetinib plus dacarbazine.ConclusionsThe combinations of selumetinib plus docetaxel and selumetinib plus dacarbazine demonstrated manageable safety and tolerability profiles and preliminary signs of clinical activity in patients with advanced solid tumors.Trial registrationClinicalTrials.gov NCT00600496; registered 8 July 2009.

P1.07-008 Lomustine Endoxan VP16 as Second or Further Line for Recurrent or Progressive Brain Metastases from SCLC

Up to fifty percent of patients with small-cell lung cancer (SCLC) will experience brain metastases (BM) during the whole course of their disease. The oral regimen Lomustine Cyclophosphamide Etoposide (LCE) has been tested in SCLC as second line treatment and was shown to be equivalent to the intravenous regimen Cyclophosphamide Adriamycin Vincristine (Gervais R et al. Clin Lung Cancer 2015;16:100-5). This retrospective study evaluates the cerebral response rate (CRR) of this oral chemotherapy on brain metastases (BM) from SCLC relapsing after platinum-based chemotherapy. Patients with disease progression after one or more prior chemotherapy regimens for SCLC were included if they had at least one measurable BM according to RECIST 1.1, with PS≤2. Patients with symptomatic BM were eligible. They were excluded if they had received previous whole brain irradiation before LCE or were receiving concomitant brain irradiation. Patients received the chemotherapy according to modalities described in the GFPC-0501 study (1). The doses were determined by a therapeutic risk level: lomustine, 80 to 120 mg on day 1, cyclophosphamide 100 mg/d, and etoposide 75 mg/d, for 6 to 14 days, every 28 days, until progression or major toxicity. Primary prophylactic granulocyte colony-stimulating factor was recommended. The primary objective was the cerebral response rate (CRR) using RECIST 1.1 .Secondary objectives included the extra-cerebral response rate (ECRR), the overall survival and the safety. From 2008 to 2014 in Baclesse comprehensive cancer center, 24 patients fulfilled the inclusion criteria. The median age was 57.5 years (interquartile range [IR] 51.5–64.5). CCR was 50% while ECRR was 26% (NS, p=0.135). Interestingly, 8 of the 9 patients with neurological symptoms had symptomatic improvement. Previous treatment (chemotherapy and/or radiotherapy) for BM did not appear to have any effect on CRR (p=1.000). The hematologic toxicities were the most common side effects with neutropenia (grade ¾ : 26%) and thrombocytopenia (grade ¾ : 21%). Median overall survival was 6.3 months. In our study, Lomustine Cyclophosphamide Endoxan has a high activity on BM from SCLC, with a comparable extra cerebral response rate than others regimen currently used in second line setting. It has a manageable toxicity profile and the oral route allows patients with a short expectancy of life to benefit from a home-delivered treatment. We suggest that this combination should be tested in a prospective study.

Appropriate use of granulocyte-colony stimulating factor in treating hematologic malignancies

Granulocyte colony stimulating factor (G-CSF) plays important roles in treating hematologic malignancies including hematopoietic stem cell transplantation (HCT) and intensive chemotherapy. In the situation of peripheral blood cell transplantation (PBSCT), G-CSF mobilizes hematopoietic stem cells and progenitor cells into peripheral blood and thereby accelerates recovery from neutropenia and thus prevents serious infections after transplantation. In the setting of chemotherapy administration for leukemia and lymphoma, G-CSF can be given to prevent febrile neutropenia (FN) in order to maintain drug intensity and thus improve therapeutic outcomes. Based upon the guidelines abroad and in our country, G-CSF should be used as primary or secondary prophylaxis according to the risk of developing FN during chemotherapy. Patients with acute leukemia who received extremely high-risk chemotherapy benefitted from prophylactic treatment with G-CSF, especially those with acute lymphoblastic leukemia. In treating lymphomas for patients given a regimen with a high risk for FN (>20%), administration of G-CSF as primary prophylaxis is recommended. In addition, administration of primary prophylactic G-CSF is also recommended for patients given a regimen with an intermediate risk for FN (10-20%), if they have risk factors for worsening FN or infection.

History of chronic comorbidity and risk of chemotherapy-induced febrile neutropenia in cancer patients not receiving G-CSF prophylaxis.

Chemotherapy-induced febrile neutropenia (FN) is a clinically important complication that affects patient outcome by delaying chemotherapy doses or reducing dose intensity. Risk of FN depends on chemotherapy- and patient-level factors. We sought to determine the effects of chronic comorbidities on risk of FN. We conducted a cohort study to examine the association between a variety of chronic comorbidities and risk of FN in patients diagnosed with six types of cancer (non-Hodgkin lymphoma and breast, colorectal, lung, ovary, and gastric cancer) from 2000 to 2009 who were treated with chemotherapy at Kaiser Permanente Southern California, a large managed care organization. We excluded those patients who received primary prophylactic granulocyte colony-stimulating factor. History of comorbidities and FN events were identified using electronic medical records. Cox models adjusting for propensity score, stratified by cancer type, were used to determine the association between comorbid conditions and FN. Models that additionally adjusted for cancer stage, baseline neutrophil count, chemotherapy regimen, and dose reduction were also evaluated. A total of 19 160 patients with mean age of 60 years were included; 963 (5.0%) developed FN in the first chemotherapy cycle. Chronic obstructive pulmonary disease [hazard ratio (HR) = 1.30 (1.07-1.57)], congestive heart failure [HR = 1.43 (1.00-1.98)], HIV infection [HR = 3.40 (1.90-5.63)], autoimmune disease [HR = 2.01 (1.10-3.33)], peptic ulcer disease [HR = 1.57 (1.05-2.26)], renal disease [HR = 1.60 (1.21-2.09)], and thyroid disorder [HR = 1.32 (1.06-1.64)] were all associated with a significantly increased FN risk. These results provide evidence that history of several chronic comorbidities increases risk of FN, which should be considered when managing patients during chemotherapy.

Severe neutropenia and relative dose intensity among patients &lt;65 and ≥65 years with non-Hodgkin’s lymphoma receiving CHOP-based chemotherapy

The objective of this study was to describe the incidence of grade 3/4 neutropenia, patterns of chemotherapy treatment, and granulocyte colony-stimulating factor (G-CSF) use patterns among patients with non-Hodgkin's lymphoma (NHL)<65 and ≥65 years. This retrospective, observational study included adult patients with NHL who received cyclophosphamide, doxorubicin, vincristine, and prednisone±rituximab (CHOP±R) from January 2006 to June 2010. A total of 1,579 patients were included, with 54.1%<65 years and 45.9%≥65 years. Most received CHOP-R on a Q3W schedule. Among patients<65 years, the incidence of grade 3/4 neutropenia was 52.3%, the mean relative dose intensity (RDI) was 80.4%, and the incidences of dose delays and reductions were 26.5 and 9.6%, respectively. Among patients≥65 years, the incidence of grade 3/4 neutropenia was 63.2%, the mean RDI was 73.9%, and the incidences of dose delays and reductions were 24.6 and 24.9%, respectively. Most patients (86.9%) received G-CSF. Among patients<65 years, 71.9, 17.4, and 10.7% first received G-CSF as primary prophylaxis, secondary prophylaxis, or treatment, respectively. Among patients≥65 years, 80.1, 11.6, and 8.3% first received G-CSF as primary prophylaxis, secondary prophylaxis, or treatment, respectively. Chemotherapy regimens and schedules were similar among age groups. Grade 3/4 neutropenia, reduced RDI, and dose delays were common in both age groups, though patients≥65 years had a higher incidence of dose reductions. In spite of these similarities, patients<65 years were less likely to receive primary prophylactic G-CSF. Thus, careful assessment of neutropenia risk factors is needed across age groups to determine appropriate G-CSF use and support planned chemotherapy.