A multicentre, randomised trial comparing schedules of G-CSF (filgrastim) administration for primary prophylaxis of chemotherapy-induced febrile neutropenia in early stage breast cancer

Open AccessPublished:April 20, 2020DOI:https://doi.org/10.1016/j.annonc.2020.04.005

      Highlights

      • Multicentre randomised trial of 466 breast cancer patients compared schedules of filgrastim administration.
      • Provides real-world data showing filgrastim use beyond 5 days did not significantly improve co-primary or secondary outcomes.
      • 5 days of filgrastim should be considered the standard of care.

      Background

      The optimal duration of filgrastim as primary febrile neutropenia (FN) prophylaxis in early breast cancer patients is unknown, with 5, 7 or 10 days being commonly prescribed. This trial evaluates whether 5 days of filgrastim was non-inferior to 7/10 days.

      Patients and methods

      In this randomised, open-label trial, early breast cancer patients who were to receive filgrastim as primary FN prophylaxis were randomly allocated to 5 versus 7 versus 10 days of filgrastim for all chemotherapy cycles. A protocol amendment in November 2017 allowed subsequent patients (N = 324) to be randomised to either 5 or 7/10 days. The primary outcome was a composite of either FN or treatment-related hospitalisations. Secondary outcomes included chemotherapy dose reductions, delays and discontinuations. Analyses were carried out by per protocol (primary) and intention-to-treat, and the non-inferiority margin was set at 3% for the risk of having FN and/or hospitalisation per cycle of chemotherapy.

      Results

      Patients (N = 466) were randomised to receive 5 (184, 39.5%), or 7/10 (282, 60.5%) days of filgrastim. In our primary analysis, the difference in risk of either FN or treatment-related hospitalisation per cycle was −1.52% [95% confidence interval (CI): −3.22% to 0.19%] suggesting non-inferiority of a 5-day filgrastim schedule compared with 7/10-days. The difference in events per cycle for FN was 0.11% (95% CI: −1.05 to 1.27) while for treatment-related hospitalisations it was −1.68% (95% CI: −2.73% to −0.63%). The overall proportions of patients having at least one occurrence of either FN or treatment-related hospitalisation were 11.8% and 14.96% for the 5- and 7/10-day groups, respectively (risk difference: −3.17%, 95% CI: −9.51% to 3.18%).

      Conclusion

      Five days of filgrastim was non-inferior to 7/10 days. Given the cost and toxicity of this agent, 5 days should be considered standard of care.

      ClinicalTrials.gov registration

      Key words

      Introduction

      Neutropenia associated with adjuvant chemotherapy for early stage breast cancer (EBC) can cause febrile neutropenia (FN), treatment-related hospitalisations, reduced patient quality of life, and lead to chemotherapy delays, dose reductions and discontinuation.
      • Renner P.
      • Milazzo S.
      • Liu J.P.
      • Zwahlen M.
      • Birkmann J.
      • Horneber M.
      Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients.
      To reduce these risks, many chemotherapy regimens are co-administered with granulocyte colony-stimulating factor (G-CSF) prophylaxis with filgrastim (Neupogen®, Grastofil®)
      Amgen Canada Inc
      Product Monograph (filgrastim).
      or pegfilgrastim (Neulasta®).
      Amgen Canada Inc
      Product monograph (pegfilgrastim).
      Due to significant differences in cost, only filgrastim is provincially funded in Ontario, Canada for patients without third party drug insurance.
      While local,
      CCO Drug FormularyGCSF Working Group
      Cancer Care Ontario GCSF Recommendations 2016.
      national
      National Comprehensive Cancer Network (NCCN)
      NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors.
      and international
      • Aapro M.S.
      • Bohlius J.
      • Cameron D.A.
      • et al.
      2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.
      ,
      • Smith T.J.
      • Bohlke K.
      • Lyman G.H.
      • et al.
      Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update.
      evidence-based guidelines recommend primary prophylaxis when the overall FN risk is >20%, there is no clear guidance on the duration of filgrastim administration.
      Amgen Canada Inc
      Product Monograph (filgrastim).
      ,
      • Hendler D.
      • Rizel S.
      • Yerushalmi R.
      • et al.
      Different schedules of granulocyte growth factor support for patients with breast cancer receiving adjuvant dose-dense chemotherapy: a prospective nonrandomized study.
      In clinical practice, the most commonly used durations are 5, 7 or 10 days, with the choice usually based on physician preference.
      • Hilton J.
      • Vandermeer L.
      • Sienkiewicz M.
      • et al.
      Filgrastim use in patients receiving chemotherapy for early-stage breast cancer-a survey of physicians and patients.
      Given that filgrastim has common side-effects (including bone pain, headaches, fever, joint and muscle pains as well as injection site pain), requires daily subcutaneous administration, and is expensive (about Can$192/dose for Neupogen and Can$144/dose for Grastofil), identification of its optimal duration is an important clinical question to both patients and health care providers.
      CCO Drug FormularyGCSF Working Group
      Cancer Care Ontario GCSF Recommendations 2016.
      ,
      • Hilton J.
      • Vandermeer L.
      • Sienkiewicz M.
      • et al.
      Filgrastim use in patients receiving chemotherapy for early-stage breast cancer-a survey of physicians and patients.
      ,
      • Fraser J.
      • Steele N.
      • Al Zaman A.
      • Yule A.
      Are patients in clinical trials representative of the general population? Dose intensity and toxicities associated with FE100C-D chemotherapy in a non-trial population of node positive breast cancer patients compared with PACS-01 trial group.
      Our team has been evaluating novel pragmatic trial models for comparisons of standard of care interventions.
      • Basulaiman B.
      • Awan A.A.
      • Fergusson D.
      • et al.
      Creating a pragmatic trials program for breast cancer patients: Rethinking Clinical Trials (REaCT).
      We previously reported a study confirming the feasibility of performing a randomised clinical trial using an oral consent methodology for comparing 5- or 7- or 10-day schedules of filgrastim.
      • Ibrahim M.F.K.
      • Hilton J.
      • Mazzarello S.
      • et al.
      A multi-center pragmatic, randomized, feasibility trial comparing standard of care schedules of filgrastim administration for primary febrile neutropenia prophylaxis in early-stage breast cancer.
      This feasibility study was expanded to compare efficacy outcomes between the 5- or 7/10-day arms. The primary outcome of a composite of FN and treatment-related hospitalisations was chosen as patients have stated these were the outcomes of greatest importance to them.
      • Hilton J.
      • Vandermeer L.
      • Sienkiewicz M.
      • et al.
      Filgrastim use in patients receiving chemotherapy for early-stage breast cancer-a survey of physicians and patients.

      Methods

       Study design and participants

      This was a randomised, open-label, non-inferiority trial carried out across seven Canadian cancer centres. Eligible patients had EBC, no prior history of chemotherapy use, were planned to receive standard neo/adjuvant chemotherapy that would include filgrastim as primary FN prophylaxis and were able to provide verbal consent. Exclusion criteria included any medical contraindication to filgrastim. Regulatory approval for this study was the Ontario Cancer Research Ethics Board. Patients were approached for study participation by their treating oncologist. This trial utilised the integrated consent model (ICM) incorporating oral consent.
      • Kim S.Y.
      • Miller F.G.
      Informed consent for pragmatic trials–the integrated consent model.

       Randomisation and masking

      Eligible and consented patients were initially randomised 1 : 1 : 1 to 5 or 7 or 10 days of filgrastim for each of their chemotherapy cycles. Following confirmation of the feasibility of the oral consent methodology (Version 14 June 14 2016, NCT02428114, N = 142), and with feedback from patients, nurses and physicians, but without seeing or performing an interim analysis of the data of the feasibility study, a protocol amendment (14 November 2017, NCT02816164) allowed subsequent patients to be randomised 1 : 1 to 5 or 7/10 days. If randomised to the 7- or 10-day arm, the choice of 7- or 10-day duration was left to the patient and treating physician. Randomisation used a permuted block design of variable block sizes of two, four and six, using a web-based application developed by The Ottawa Methods Centre, with stratification by centre. The dose, start date of treatment and brand of filgrastim prescribed was left to the individual patient and physician, including the use of biosimilars.

       Procedures

      Patients received filgrastim (Neupogen, Amgen, Thousand Oaks, CA, USA, and Grastofil, Apotex, Toronto, ON, Canada) for each cycle of chemotherapy as primary FN prophylaxis. Follow-up visits occurred as per usual care as the study did not mandate visit schedules. Outcome data were collected from case report forms completed by the physician when the patient was seen in clinic as well as from the patient's electronic health records. Adverse events were collected according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

       Outcomes

      The primary outcome was a composite measure of either documented, laboratory-confirmed, FN (an absolute neutrophil count <0.5 × 109/l with oral temperature >38.3°C or two consecutive readings >38.0°C for 2 h)
      • de Naurois J.
      • Novitzky-Basso I.
      • Gill M.J.
      • et al.
      Management of febrile neutropenia: ESMO Clinical Practice Guidelines.
      or treatment-related hospital admission, measured as a complication rate per cycle of chemotherapy. Secondary outcomes of interest were the proportion of patients who required chemotherapy dose delay/reduction and discontinuation. As patient surveys indicated that FN, hospitalisation and chemotherapy dose delays/reductions and discontinuations were considered as being important,
      • Hilton J.
      • Vandermeer L.
      • Sienkiewicz M.
      • et al.
      Filgrastim use in patients receiving chemotherapy for early-stage breast cancer-a survey of physicians and patients.
      data were analysed as the frequency of events per cycle, and the proportion of patients with at least one event during treatment.

       Sample size

      We made the following assumptions for our sample size estimate: based on the results of previous reviews evaluating the risk of FN when receiving primary FN prophylaxis with chemotherapy for EBC,
      • Madarnas Y.
      • Dent S.F.
      • Husain S.F.
      • et al.
      Real-world experience with adjuvant fec-d chemotherapy in four Ontario regional cancer centres.
      • Younis T.
      • Rayson D.
      • Thompson K.
      Primary G-CSF prophylaxis for adjuvant TC or FEC-D chemotherapy outside of clinical trial settings: a systematic review and meta-analysis.
      • Vandenberg T.
      • Younus J.
      • Al-Khayyat S.
      Febrile neutropenia rates with adjuvant docetaxel and cyclophosphamide chemotherapy in early breast cancer: discrepancy between published reports and community practice-a retrospective analysis.
      • Soong D.
      • Haj R.
      • Leung M.G.
      • et al.
      High rate of febrile neutropenia in patients with operable breast cancer receiving docetaxel and cyclophosphamide.
      all groups were expected to have a 5% total risk of a primary outcome event per cycle of chemotherapy and there was a constant risk during each cycle of chemotherapy, which was measured as a repeated measure assuming a constant within-subject correlation of 0.01.
      • Donner A.
      • Shoukri M.M.
      • Klar N.
      • Bartfay E.
      Testing the equality of two dependent kappa statistics.
      With these assumptions, the required overall size was 213 patients per arm for a total of 426 patients (1704 expected cycles). To account for 5% non-compliance with the protocol, the total sample size required was set at 466 patients. Medical oncologists were surveyed in their non-inferiority margin preference
      • Hilton J.
      • Vandermeer L.
      • Sienkiewicz M.
      • et al.
      Filgrastim use in patients receiving chemotherapy for early-stage breast cancer-a survey of physicians and patients.
      and a non-inferiority margin of 3% was set based on these results.

       Statistical analysis

      Baseline characteristics by group are presented with means (continuous measures) or proportions (categorical or ordinal data) with 95% confidence intervals (CIs). The primary analysis of the primary composite outcome was a per-protocol (PP) analysis, including randomised participants who complied with their allocated group for the duration of the study, which is preferred for non-inferiority trials. In addition, we conducted supportive analyses using the intention-to-treat (ITT) principle, consisting of all patients according to the randomised schedule regardless of compliance. The primary analyses used longitudinal repeated measures analysis to determine the number of events of our primary outcome (FN/hospitalisation) in each of the groups (5 days, versus 7/10 days). Risk differences and 95% CIs were calculated such that values less than 0 indicate a lower rate of events per cycle in the 5-day group compared with the 7/10-day group. For primary analysis of the primary outcome, the risk difference between groups was compared using a one-sided Z-test (one-sided alpha of 0.025). The CI was computed as the risk in the 5-day group minus the risk in the 7/10-day group and compared against our non-inferiority margin of 3%. The proportion of patients experiencing at least one event at any time during the study was also reported.
      All statistical analyses were carried out using SAS Software Version 9.3 (SAS Institute Inc., Cary, NC, USA).

      Results

      A total of 466 patients were randomised between May 2015 and September 2018, including 142 from our feasibility trial. The CONSORT flow diagram is shown in Figure 1. The baseline characteristics of the randomised patients were balanced (Table 1). The median age was 56 years (range 23–89 years), and 22.5% of patients (105/466) were ≥65 years of age at randomisation. The most common chemotherapy regimens were: docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks for four cycles (TC: 158/466, 33.9%), doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 2 weeks for four cycles followed by paclitaxel 175 mg/m2 every 2 weeks for four cycles (dose-dense AC-paclitaxel: 135/466, 29%), fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for three cycles, then docetaxel 100 mg/m2 every 3 weeks for three cycles (FEC-D) with filgrastim from cycle 4 (98/466, 21%) and FEC-D with filgrastim from cycle 1 (32/466, 6.9%). The dose of G-CSF prescribed was available for 465 patients (99.8%), and was 300 μg (97.2%) and 480 μg (2.6%), respectively. There were 39.5% (184/466) and 60.5% (282/466) patients randomly allocated to the 5- and 7/10-day arms, respectively. Of randomly allocated patients, 14 were not compliant with their randomised treatment allocation due to: discovery of metastatic disease (n = 3), consent withdrawal (n = 2), patient did not want G-CSF injections (n = 4), prescribed pegfilgrastim (n = 3) and declined chemotherapy (n = 2).
      Figure thumbnail gr1
      Figure 1Study CONSORT diagram.
      PP, per protocol; Pt, patient.
      Table 1Baseline characteristics
      CharacteristicPer protocolIntention-to-treat
      Overall5 days7/10 daysOverall5 days7/10 days
      n (%)401153 (38.2%)248 (61.8%)466184 (39.5%)282 (60.5%)
      Median age (range) (years)57 (23–89)56 (24–79)57 (57–89)56 (23–89)56 (23–85)56 (23–89)
      Proportion ≥65 years of age, n (%)93 (23.2)28 (18.3)65 (26.2)105 (22.5)34 (18.5)71 (25.2)
      Chemotherapy regimen
       TC142 (35.4%)46 (30.1%)96 (38.7%)158 (33.9%)51 (27.7%)107 (37.9%)
       FEC-D (filgrastim from cycle 1)30 (4.5%)10 (6.5%)20 (8.1%)32 (6.9%)11 (6.0%)21 (7.4%)
       FEC-D (filgrastim from cycle 4)90 (22.4%)37 (24.2%)53 (21.4%)98 (21.0%)40 (21.7%)58 (20.6%)
       Dose-dense AC-paclitaxel109 (27.2%)50 (32.7%)59 (23.8%)135 (29.0%)64 (34.8%)71 (25.2%)
       AC6 (1.5%)2 (1.3%)4 (1.6%)11 (2.4%)6 (3.3%)5 (1.8%)
       TC-H17 (4.2%)5 (3.3%)12 (4.8%)24 (5.2%)8 (4.3%)16 (5.7%)
       Other7 (1.7%)3 (2.0%)4 (1.6%)8 (1.7%)4 (2.2%)4 (1.4%)
      Dose of filgrastim
       300 μg391 (97.5%)148 (96.7%)243 (98.0%)453 (97.2%)178 (96.7%)275 (97.5%)
       480 μg10 (2.5%)5 (3.3%)5 (2.0%)12 (2.6%)6 (3.3%)6 (2.1%)
      TC = docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks for four cycles.
      FEC-D = 5-fluorouracil 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 every 3 weeks for three cycles, then docetaxel 100 mg/m2 every 3 weeks for three cycles.
      ddAC-P = doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 every 2 weeks for four cycles followed by paclitaxel 175 mg/m2 every 2 weeks for four cycles.
      AC = doxorubicin 60 mg/m2 plus cyclophosphamide 60 mg/m2 every 3 weeks for four cycles.
      TC-H = docetaxel 75 mg/m2, carboplatin area under the curve of six plus trastuzumab every 3 weeks for six cycles.
      All regimens could include trastuzumab if that was being prescribed.
      The 184 patients in the 5-day arm received a total of 897 cycles, while the 282 patients in the 7/10-day arm received 1302 total cycles of chemotherapy.
      The risk of our primary composite outcome of either FN or treatment-related hospitalisation was 2.09% per cycle in the 5-day schedule compared with 3.60% in the 7/10-day schedule (Table 2), resulting in a difference in risks of the primary composite outcome per cycle of −1.52% (95% CI: −3.22% to 0.19%) suggesting non-inferiority of the 5-day filgrastim schedule compared with the 7/10-day schedule. In the ITT analysis, the difference in risks was −0.78% per cycle (95% CI: −2.47% to 0.91%) also suggesting non-inferiority of the 5-day filgrastim schedule (supplementary Table S1, available at Annals of Oncology online). For FN alone, the PP difference in risks per cycle was 0.11% (95% CI: −1.05% to −1.27%) (Table 2), while the difference in risks per cycle was −1.68% (95% CI: −2.73% to −0.63%) for treatment-related hospitalisations, indicating increased treatment-related hospitalisations with 7/10-day schedules (Table 2). The causes of treatment-related hospitalisations other than FN are provided in supplementary Table S2, available at Annals of Oncology online.
      Table 2Clinical outcome data (repeated measures) presented by events per cycle: per protocol analysis
      Intervention group
      5 days7/10 days
      Number of patients153248
      Number of cycles7541152
      EventsEvents/cycle (%)

      (95% CI)
      EventsEvents/cycle (%)

      (95% CI)
      Risk difference (95% CI)
      Primary composite outcome
       Febrile neutropenia101.38% (0.45 to 2.31)141.26% (0.57 to 1.96)0.11% (−1.05 to 1.27)
       Treatment-related hospitalisation50.66% (0.09 to 1.24)272.34% (1.47 to 3.22)−1.68% (−2.73 to −0.63)
       Either152.09% (0.84 to 3.33)403.60% (2.44 to 4.76)−1.52% (−3.22 to 0.19)
      Secondary composite outcome
       Chemotherapy dose reduction344.54% (3.00 to 6.07)655.68% (4.28 to 7.08)−1.14% (−3.22 to 0.93)
       Chemotherapy dose delay141.81% (0.80 to 2.83)292.46% (1.48 to 3.44)−0.65% (−2.06 to 0.76)
       Chemotherapy discontinuation212.75% (1.62 to 3.88)403.42% (2.39 to 4.45)−0.67% (−2.19 to 0.86)
       Either648.59% (6.46 to 10.72)11610.26% (8.38 to 12.15)−1.68% (−4.53 to 1.17)
      CI, confidence interval.
      The overall proportions of patients having at least one occurrence of either FN or treatment-related hospitalisation were 11.8% and 14.96% for the 5- and 7/10-day groups, respectively (risk difference: −3.17%, 95% CI: −9.51% to 3.18%) (Table 3). The overall proportions of patients having at least one occurrence of FN were 9.55% and 5.84% for the 5- and 7/10-day groups, respectively (risk difference: 3.71%, 95% CI: −1.42% to 8.84%) (Table 3). The overall proportions of patients having at least one treatment-related hospitalisation were 3.37% and 10.95% for the 5- and 7/10-day groups, respectively (risk difference: −7.58%, 95% CI: −12.13% to −3.03%) (Table 3). Finally, the risk per cycle of chemotherapy dose delays, dose reduction or discontinuation was 8.59% and 10.26%, respectively. The difference in risk was −1.68% (95% CI: −4.53% to 1.17%) (Table 2).
      Table 3Clinical outcome data (repeated measures) presented by patient: per protocol and intention-to-treat analysis
      Per protocol analysisIntention-to-treat analysis
      Intervention groupRisk difference (95% CI)Intervention groupRisk difference (95% CI)
      5 days7/10 days5 days7/10 days
      n = 153n = 248n = 178n = 274
      Events (%)Events (%)Events (%)Events (%)
      Primary composite outcome
       Febrile neutropenia9 (5.88%)13 (5.24%)0.64% (−4.01 to 5.29)17 (9.55%)16 (5.84%)3.71% (−1.42 to 8.84)
       Treatment-related hospitalisation5 (3.27%)27 (10.89%)−7.61% (−12.41 to −2.83)6 (3.37%)30 (10.95%)−7.58% (−12.13 to −3.03)
       Either12 (7.84%)36 (14.52%)−6.67% (−12.79 to −0.56)21 (11.8%)41 (14.96%)−3.17% (−9.51 to 3.18)
      Secondary composite outcome
       Chemotherapy dose reduction30 (19.61%)56 (22.58%)−2.97% (−11.14 to 5.19)34 (19.10%)67 (24.45%)−5.35% (−13.05 to 2.35)
       Chemotherapy dose delay12 (7.84%)24 (9.68%)−1.83% (−7.46 to 3.79)24 (13.48%)28 (10.22%)3.26% (−2.90 to 9.43)
       Chemotherapy discontinuation21 (13.73%)40 (16.13%)−2.40% (−9.52 to 4.72)23 (12.92%)43 (15.69%)−2.77% (−9.32 to 3.77)
       Either53 (34.64%)93 (37.5%)−2.86 (−12.51 to 6.79)67 (37.64%)108 (39.42%)−1.78% (−10.95 to 7.40)
      Regarding the secondary outcomes, for the 5- or 7/10-days schedules of filgrastim, the aggregate incidence risks of chemotherapy delays per cycle were 1.81% and 2.46%, respectively (risk difference −0.65%, 95% CI: −2.06% to 0.76%) (Table 2). The risks of chemotherapy dose reductions for the 5- or 7/10-days of filgrastim groups per cycle were 4.54% and 5.68%, respectively (risk difference −1.14%, 95% CI: −3.22% to 0.93%) (Table 2). The risks of chemotherapy discontinuations per cycle were 2.75% and 3.42%, respectively (risk difference −0.67%, 95% CI: −2.19% to 0.86%) (Table 2). The complete list of reasons for hospitalisations, chemotherapy reductions, chemotherapy delays and chemotherapy discontinuations is shown in supplementary Table S2, available at Annals of Oncology online.
      The overall proportions of patients having at least one occurrence of either chemotherapy dose delay or reduction or discontinuation were 37.64% and 39.42% for the 5- and 7/10-day groups, respectively (risk difference: −1.78%, 95% CI: −10.95% to 7.40%) (Table 3). The overall proportions of patients having at least one occurrence of either a dose delay, dose reduction or discontinuation were 13.48% and 10.22% for the 5- and 7/10-day groups, respectively (risk difference: 3.26%, 95% CI: −2.90% to 9.43%) (Table 3).
      In regards to G-CSF schedule changes, there were totals of 1/897 (0.11%) in the 5-day group and 38/1302 (2.92%) in the 7/10-day group that had filgrastim schedules decreased (supplementary Table S3, available at Annals of Oncology online). The main reasons for the decreases were muscle/joint pain and high neutrophil levels. In contrast, filgrastim schedule increases occurred in 21/897 (2.34%) and 7/1302 (0.54%) cycles in the 5- and 7/10-day arms, respectively (supplementary Table S3, available at Annals of Oncology online). Lastly, 5/897 (0.56%) in the 5-day arm and 5/1302 (0.38%) in the 7/10-day arm had filgrastim completely discontinued, due mainly to patient choice.

      Discussion

      Despite its considerable cost and widespread use for two decades, the most effective duration of filgrastim as primary FN prophylaxis for EBC patients has remained unknown.
      • Fernandes R.
      • Mazzarello S.
      • Stober C.
      • et al.
      Primary febrile neutropenia prophylaxis for patients who receive FEC-D chemotherapy for breast cancer: a systematic review.
      This may in part reflect the fact that many studies in the literature are retrospective in nature with resulting methodological challenges.
      • Aapro M.S.
      • Bohlius J.
      • Cameron D.A.
      • et al.
      2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours.
      • Smith T.J.
      • Bohlke K.
      • Lyman G.H.
      • et al.
      Recommendations for the use of WBC growth factors: American Society of Clinical Oncology Clinical Practice Guideline Update.
      • Hendler D.
      • Rizel S.
      • Yerushalmi R.
      • et al.
      Different schedules of granulocyte growth factor support for patients with breast cancer receiving adjuvant dose-dense chemotherapy: a prospective nonrandomized study.
      ,
      • Madarnas Y.
      • Dent S.F.
      • Husain S.F.
      • et al.
      Real-world experience with adjuvant fec-d chemotherapy in four Ontario regional cancer centres.
      • Younis T.
      • Rayson D.
      • Thompson K.
      Primary G-CSF prophylaxis for adjuvant TC or FEC-D chemotherapy outside of clinical trial settings: a systematic review and meta-analysis.
      • Vandenberg T.
      • Younus J.
      • Al-Khayyat S.
      Febrile neutropenia rates with adjuvant docetaxel and cyclophosphamide chemotherapy in early breast cancer: discrepancy between published reports and community practice-a retrospective analysis.
      • Soong D.
      • Haj R.
      • Leung M.G.
      • et al.
      High rate of febrile neutropenia in patients with operable breast cancer receiving docetaxel and cyclophosphamide.
      ,
      • Weycker D.
      • Barron R.
      • Edelsberg J.
      • Kartashov A.
      • Legg J.
      • Glass A.G.
      Risk and consequences of chemotherapy-induced neutropenic complications in patients receiving daily filgrastim: the importance of duration of prophylaxis.
      • Altwairgi A.K.
      • Hopman W.M.
      • Mates M.
      Real-world impact of granulocyte-colony stimulating factor on febrile neutropenia.
      • von Minckwitz G.
      • Kummel S.
      • du Bois A.
      • et al.
      Pegfilgrastim ± ciprofloxacin for primary prophylaxis with TAC (docetaxel/doxorubicin/cyclophosphamide) chemotherapy for breast cancer. Results from the GEPARTRIO study.
      To our knowledge, this is the only randomised trial to prospectively answer this important clinical question. Our study showed that 5 days was non-inferior to 7 or 10 days of filgrastim use. Given the recognised toxicity and cost of this agent, as well as the impact on health economics and patient morbidity, the shorter duration should be considered standard of care.
      It is challenging to compare our findings with those in the literature as studies vary in the type of outcome (e.g. FN rates, neutropenia rates), the different chemotherapy regimens (e.g. doses and dosing intervals) and type of analysis (e.g. by proportion of patients or per cycle of chemotherapy) reported.
      In the current study, the choice of primary and secondary outcomes was driven by the findings of a survey in which patients rated FN and treatment-related hospitalisation as being equally important to them.
      • Hilton J.
      • Vandermeer L.
      • Sienkiewicz M.
      • et al.
      Filgrastim use in patients receiving chemotherapy for early-stage breast cancer-a survey of physicians and patients.
      In addition, as outcome events can be expressed by the rate in the study population overall, but also by the total number of chemotherapy cycles received, we therefore presented both. Interestingly, the overall proportions of patients having at least one occurrence of any of the study outcomes were 41.01% and 43.43% for the 5- and 7/10-day groups, respectively. Thus, despite the use of primary filgrastim prophylaxis in all patients, events are common.
      There are acknowledged limitations with our trial. The observed number of events in both arms was lower (3.60% and 2.09% per cycle) than what was initially hypothesised (5% per cycle). This would result in increased statistical power to declare non-inferiority of the 5-day intervention.
      Due to the study's pragmatic nature, it was not double-blind in design. On the other hand, our pragmatic design allowed us to report more accurately on real-world practice. The average age of patients in the current study was 56 (range 23–89 years) with 22.5% (105/466) being 65 years of age or older.
      • Madarnas Y.
      • Dent S.F.
      • Husain S.F.
      • et al.
      Real-world experience with adjuvant fec-d chemotherapy in four Ontario regional cancer centres.
      • Younis T.
      • Rayson D.
      • Thompson K.
      Primary G-CSF prophylaxis for adjuvant TC or FEC-D chemotherapy outside of clinical trial settings: a systematic review and meta-analysis.
      • Vandenberg T.
      • Younus J.
      • Al-Khayyat S.
      Febrile neutropenia rates with adjuvant docetaxel and cyclophosphamide chemotherapy in early breast cancer: discrepancy between published reports and community practice-a retrospective analysis.
      • Soong D.
      • Haj R.
      • Leung M.G.
      • et al.
      High rate of febrile neutropenia in patients with operable breast cancer receiving docetaxel and cyclophosphamide.
      As age ≥65 is a factor for increased risk of FN, in an unplanned analysis we compared FN rates for patients younger and older than 65. The proportion of patients having FN was 23/100 (6.5%) versus 10/100 (10%) for <65 and ≥65 groups (P value = 0.24).
      As with all trials, an important issue is that of bias. In the current study such bias can come from the unbalanced numbers of patients in the PP and ITT groups. There were 65 patients (roughly 14%) who were enrolled in the study but not included in the PP primary analysis. There were 46 events in the ITT analysis for 7/10 days, which went to 40 events in the PP analysis (13% decline). This is with a 12% decline in the number of cycles included. There were 25 events in the ITT analysis for 5 days, which went to 15 events in the PP analysis (40% decline). This is with a 16% decline in the number of cycles included in the analysis. Further, 21 patients were initially enrolled in the 5-day arm, but received treatment for >5 days, which reflects both the challenges and importance of pragmatic trials as they reflect the realities of clinical practice. There were therefore more primary outcome events in the ITT analysis that were excluded from the PP analysis in the 5-day arm than in the 7-day arm. This reflects the real-world nature of this trial and that for many and often diverse reasons attrition occurs, and that patients do not always receive the same treatment as initially prescribed. However, in both analyses, the 95% CI for the risk ratio did not include the boundary of interest and the study conclusion would be to declare non-inferiority regardless of the analysis population used. Hence, it is possible that this difference was due to chance, and the effect of this difference does not appear to be significant. Our studies also allowed patients to receive biosimilar formulations of filgrastim again making the results more generalisable.
      A further limitation of the study is the uneven distribution of patients between 7 and 10 days of filgrastim. As mentioned, the combination of 7 and 10 was driven by comments from patients and health care professions. With hindsight, this imbalance could have been mitigated to some degree if we had introduced some form of biased-coin randomisation into the expanded cohort of patients.
      Future studies are needed to further evaluate whether even shorter durations can be used, e.g. filgrastim given on alternate days for three injections is used in some practices. In addition, the role of primary prophylaxis with G-CSF compared with oral antibiotics is also being explored in other trials.
      • Clemons M.
      • Mazzarello S.
      • Hilton J.
      • et al.
      Feasibility of using a pragmatic trials model to compare two primary febrile neutropenia prophylaxis regimens (ciprofloxacin versus G-CSF) in patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer (REaCT-TC).
      Future studies could also use patient-reported outcomes to address the toxicity of different durations of G-CSF, something that was not done in the current study.
      In conclusion, identifying the most effective duration of filgrastim administration will improve patient comfort and acceptability, and may offer cost savings. In order to answer these important pragmatic questions, a novel method to allow comparison of established standards of care is needed as part of an increasing internationally mandated incentive to perform more pragmatic clinic trials. In the current study, we have demonstrated that 5 days of filgrastim was non-inferior to 7/10 days. Given the cost and toxicity of this agent, 5 days can be considered standard of care for breast cancer patients receiving commonly used adjuvant chemotherapy regimens.

      Acknowledgements

      The REaCT Program is supported by The Ottawa Hospital Foundation and its generous donors, particularly to Gina Mertikas-Lavictoire and the Mertikas family for their generous donation. We are grateful for patients and their families for their assistance with this study, as well as physicians for approaching patients. Highest accrual by physician was: Clemons (213), Hilton (70), Simos (25), Mates (24), Robinson (18), Califaretti (15), Zibdawi (11), Bahl (9), Raphael (7), DeCarolis (7), Tsvetkova (6), Ibrahim (6), Dr Dent (6) and Dr Hsu (6).

      Funding

      This work was supported by the Rethinking Clinical Trials Program (REaCT) at the Ottawa Hospital. Additional support was obtained from a CIHR-SPOR grant and a Cancer Care Ontario (no grant number)–Clinical Programs and Quality Initiatives grant (Government of Ontario, 2017 and 2018 competitions) to support expansion of REaCT trials to other cancer centres in Ontario.

      Disclosure

      MC and AA have received honoraria for speaking at a meeting funded by Apotex. DS participates on an advisory board for Genomic Health. AA participates on an advisory board for Novartis. BH consults for Cornerstone Research. The other authors declare no competing interests.

      Supplementary data

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