Recommendations for the Use of White Blood Cell Growth Factors: American Society of Clinical Oncology Clinical Practice Guideline Update

Home , Ancestim, Filgrastim, Lenograstim, Pegfilgrastim, Sargramostim

Table of Contents

Data Supplement 1: Evidence tables by clinical question (study design, objectives, population, intervention, and results)

Data Supplement 2: Additional Evidence Tables: Quality results for RCTs

Data Supplement 3: Search Strategy String and Dates

Data Supplement 4: QUOROM Diagram

Data Supplement 5: Clinical Questions

Data Supplement 1: CSF Evidence Tables

Clinical Question 1, Primary Prophylaxis (page 3)

Clinical Question 2: Secondary prophylaxis (page 17)

Clinical Question 3, Therapeutic CSF (page 18)

Clinical Question 4, Dose-Dense (page 20)

Clinical Question 5, Stem-cell Transplantation (page 39)

Clinical Question 6, Acute leukemia, MDS (no table; not being addressed)

Clinical Question 7, Concomitant Chemotherapy and Radiation Therapy (page 53)

Clinical Question 8, Older Adults (page 54)

Clinical Question 9, Kids (page 56)

Clinical Question 10, Administration and Dosing of CSFs (page 62)

Clinical Question 11, Comparative Efficacy (page 70)

Clinical Question 12, Radiation Injury (page 84)

Clinical Question 1, Primary Prophylaxis Author, year Publication Objectives Methods Results Conclusions type

1 NCCN 2014 Guideline To provide Primarily addresses adult patients Process starts with guidelines on the with solid tumors and non-myeloid risk assessment. use of myeloid malignancies Consider disease growth factors. type, chemotherapy regimen, patient risk factors, and treatment intent. Recommends prophylactic CSF if FN risk is ≥20%. Vehreschild Guideline To provide Comprehensive literature search Confirmed many key 20142 evidence-based and expert panel consensus recommendations recommendations given by international for the use of G- guidelines. Evidence CSF, pegylated G- for growth factors CSF, and during acute myeloid biosimilars to leukemia induction prevent infectious chemotherapy complications in and pegfilgrastim use cancer patients in hematological undergoing malignancies was chemotherapy, rated lower compared including those with with other guidelines. hematological malignancies

Author, year Publication Objectives Methods Results Conclusions type

Lyman Meta- To provide a 59 RCTs with 61 separate RR for mortality All-cause mortality is 3 2013 analysis systematic review comparisons. reduced in patients and evidence Group 1 (same dose receiving summary of the Considered studies of cancer and schedule of chemotherapy with impact of G-CSF patients receiving conventional chemotherapy): primary G-CSF support on dose chemotherapy for solid RR=0.96, 95% CI 0.92 support. The greatest chemotherapydose tumors or malignant lymphoma and to 1.01 impact was observed intensity and randomized to primary G-CSF in RCTs in patients overall mortality. support in one arm versus a control Group 2 (dose-dense receiving dose-dense group without initial G-CSF. chemotherapy in one schedules arm): RR=0.89, 95% CI 0.85 to 0.94

Group 3 (dose- escalated chemotherapy in one arm): RR=0.92, 95% CI 0.85- 0.99

Group 4 (substitution or addition of a drug in one arm): RR=0.94, 95% CI 0.89- 0.99

Overall: RR=0.93, 95% CI 0.90- 0.96

Author, year Publication Objectives Methods Results Conclusions type

Kirshner RCT To assess an Study population: adults with a Mean AUC for pain Naproxen at a dose 4 2012 intervention for diagnosis of nonmyeloid cancer, Naproxen: 6.04 of 500 mg twice per pegfilgrastim- scheduled for their first dose of Placebo: 7.71 day is effective in induced bone pain. pegfilgrastim on day 2, 3, or 4 of p=0.037 reducing the their chemotherapy cycle incidence and Maximum pain severity of Intervention: Naproxen vs placebo Naproxen: 2.59 pegfilgrastim-induced in patients receiving pegfilgrastim. Placebo: 3.40 bone pain. Naproxen (500 mg two times per p=0.005 day) on the day of pegfilgrastim and continuing for 5 to 8 days after Overall pain incidence pegfilgrastim Naproxen: 61.1% Placebo:71.3%

p=0.020 Sample size: Arm 1: 257

Arm 2: 253 Pain duration Naproxen: 1.92 days Placebo: 2.40 days p=0.009

Severe pain incidence Naproxen: 19.2% Placebo:27.0% p=0.048

Author, year Publication Objectives Methods Results Conclusions type

Renner Meta- To assess the Selected RCTs comparing CSFs Proportion of patients In patients with breast 20125 analysis effect of (any dose) with placebo or no with FN: RR 0.27; 95% cancer receiving prophylactic treatment in patients with breast CI 0.11 to 0.70 (with chemotherapy, CSFs colony-stimulating cancer at any stage, at risk of heterogeneity) have shown evidence factors (CSFs) in developing FN while undergoing of bene fi t in the reducing the any type of chemotherapy. Infection-related prevention of FN. incidence and mortality: There is evidence, duration of FN, and RR 0.14; 95% CI 0.02 though less reliable, all-cause and to 1.29 of a decrease of all- Included eight RCTs, involving 2156 infection-related cause mortality during participants, carried out between mortality during Risk for hospitalization: chemotherapy and a 1995 and 2008. chemotherapy in RR 0.14; 95% CI 0.06 reduced need for patients with breast to 0.30 hospital care. No cancer reliable evidence was IV antibiotics: found for a reduction RR 0.35; 95% CI 0.22 of infection-related to 0.55 mortality, a higher dose intensity of chemotherapy with CSFs or diminished rates of severe neutropenia and infections. The majority of adverse events reported from CSF use were bone pain and injection-site reactions but no conclusions could be drawn regarding late- term side effects.

Author, year Publication Objectives Methods Results Conclusions type

Aapro 20116 Guideline To update EORTC Systematic literature review up to Recommends that patient-related adverse risk guidelines for the July 2009. factors, such as elderly age (>/=65 years) and use of granulocyte- neutrophil count be evaluated in the overall colony stimulating assessment of FN risk before administering factor to reduce the each cycle of chemotherapy. It is important that Excluded studies of children, cost incidence of after a previous episode of FN, patients receive analyses, studies of leukemia. chemotherapy- prophylactic administration of G-CSF in induced febrile subsequent cycles. neutropenia in adult patients with Prophylactic G-CSF continues to be lymphoproliferative recommended in patients receiving a disorders and solid chemotherapy regimen with high risk of FN. tumors When using a chemotherapy regimen associated with FN in 10-20% of patients, particular attention should be given to patient- related risk factors that may increase the overall risk of FN. In situations where dose-dense or dose-intense chemotherapy strategies have survival benefits, prophylactic G-CSF support is recommended. Similarly, if reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis, primary G-CSF prophylaxis may be used to maintain chemotherapy. Clinical evidence shows that filgrastim, lenograstim and pegfilgrastim have clinical efficacy and we recommend the use of any of these agents to prevent FN and FN-related complications where indicated. Filgrastim biosimilars are also approved for use in Europe.

Author, year Publication Objectives Methods Results Conclusions type

Cooper Meta- To assessed the Assessed 20 studies of primary G- Reduction in FN Primary prophylaxis 20117 analysis effectiveness of G- CSF prophylaxis with no primary G- incidence with primary with G-CSFs CSFs pegfilgrastim, CSF prophylaxis: five studies of versus no primary G- significantly reduces filgrastim or pegfilgrastim; ten of filgrastim; and CSF FN incidence in lenograstim) in five of lenograstim. adults undergoing reducing FN Pegfilgrastim: chemotherapy for incidence in adults Five studies compared pegfilgrastim RR 0.30, 95% CI 0.14 solid tumors or undergoing with filgrastim to 0.65 lymphoma. chemotherapy for Pegfilgrastim reduces solid tumors or Filgrastim: FN incidence to a lymphoma. RR 0.57, 95% 0.48 to significantly greater 0.69 extent than filgrastim.

Lenograstim: RR 0.62, 95% CI 0.44 to 0.88

Pegfilgrastim vs filgrastim RR 0.66, 95% CI 0.44 to 0.98

Author, year Publication Objectives Methods Results Conclusions type

Kuderer Meta- To assess primary 17 RCTs Febrile neutropenia Confirmed that 20118 analysis prophylaxis with G- G-CSF: 22.4% primary prophylaxis CSF in adults with Control: 39.5% with G-CSF a solid tumor or RR=0.54, 95% CI 0.43 significantly reduces

malignant to 0.67 the risk of FN in lymphoma patients undergoing Infection-related conventional mortality chemotherapy across G-CSF: 1.5% a broad range of Control: 2.8% baseline risk. RR=0.55, 95% CI 0.34- 0.90 There was a reduction in infection- Early all-cause mortality related and all-cause G-CSF: 3.4% early mortality in Control: 5.7% patients randomized RR=0.60, 95% CI 0.43- to receive primary 0.83 prophylaxis with G- CSF. Relative dose intensity G-CSF: median 95.5% Control: median 88.5%

Bone and musculoskeletal pain G-CSF: 19.6% Control: 10.4% RR=4.02, 95% CI 1.56- 7.52

Author, year Publication Objectives Methods Results Conclusions type

Wildiers Systematic To help define the English-language publications Many breast cancer 20119 review impact of relative between 1995 and 2008 evaluating patients do not dose intensity (RDI) standard 3- or 4-weekly achieve planned RDI. and the role of chemotherapy regimens. Older age, obesity growth factor and febrile support on 30 breast cancer studies and 15 neutropenia are outcomes in breast lymphoma studies. associated with cancer and reduced RDI, which aggressive non- leads to worse Hodgkin's survival in several lymphoma studies, particularly those including anthracyclines. G- CSF prophylaxis improved RDI in most, but not all, studies.

Lyman Meta- To evaluate the risk Searched through October 2008. The RR for all-cause mortality Delivered 201010 analysis of acute myeloid associated with G-CSF was chemotherapy dose- Eligibility included solid tumor or 0.897 (95% CI, 0.857 to leukemia (AML) or 0.938) intensity and risk of myelodysplastic lymphoma patients randomly AML/MDS are syndrome (MDS) assigned to chemotherapy with or Greater RR reduction for increased but all- and overall without G-CSF support, > or = 2 mortality was seen for both cause mortality is years of follow-up, and reporting larger studies (P = .05) and mortality in patients greater chemotherapy dose- decreased in patients receiving AML/MDS or all second intensity (P = .012). receiving chemotherapy with malignancies. chemotherapy with G- or without G-CSF RR for AML/MDS associated CSF support. Greater In the 25 eligible RCTs, 6,058 and with G-CSF support was 1.92 reductions in mortality 6,746 patients were randomly (95% CI, 1.19 to 3.07) were observed with assigned to receive chemotherapy The AR increase of AML/MDS greater chemotherapy with and without initial G-CSF among patients randomly dose-intensity. support, respectively assigned to G-CSF was four per 1,000 patients (AR 0.41%; 95% CI, 0.10% to 0.72%)

Author, year Publication Objectives Methods Results Conclusions type

Herbst Systematic To compare Randomized controlled trials Both trials showed non- There is no evidence 200911 review prophylactic comparing prophylaxis with G-CSF significant results for or against antibiotics or G(M)- or GM-CSF versus antibiotics in favoring antibiotics for antibiotics compared CSF for the cancer patients of all ages receiving the prevention of fever to G(M)-CSFs for the prevention of chemotherapy or bone marrow or or hospitalization for prevention of infections and stem cell transplantation were febrile neutropenia. infections in cancer improvement of included for review. Both study patients survival in cancer arms had to receive identical patients undergoing chemotherapy regimens and other chemotherapy supportive care.

Searched 1980-2007

Two studies were included (total of 195 patients)

Author, year Publication Objectives Methods Results Conclusions type

Bohlius Meta- To assess whether Searched January 1980-April 2008 G-CSF/GM-CSF versus no G-CSF and GM-CSF, 200812 analysis G-CSF and GM- prophylaxis when used as a Randomized controlled trials CSF improve dose Severe neutropenia: prophylaxis in intensity, tumor comparing prophylaxis with G-CSF RR 0.67; 95% CI 0.60 to 0.73 patients with response, and or GM-CSF versus placebo/no malignant lymphoma overall survival in prophylaxis in adult patients with Febrile neutropenia: undergoing malignant lymphoma undergoing RR 0.74; 95% CI 0.62 to 0.89 patients with conventional malignant chemotherapy were included for Infection: chemotherapy, lymphoma review. Both study arms had to RR 0.74; 95% CI 0.64 to 0.85 reduce the risk of receive identical chemotherapy and neutropenia, febrile supportive care Intravenous antibiotics: RR 0.82; 95%CI 0.57 to 1.18 neutropenia and infection. However, Included 13 RCTs with a total of Infection-related mortality: based on the 2607 patients. RR 0.93; 95% CI 0.51 to 1.71 randomized trials OS: currently available, HR 0.97; 95% CI 0.87 to 1.09 there is no evidence that either G-CSF or Freedom from treatment GM-CSF provide a failure: HR 1.11; 95% CI 0.91 to 1.35 significant advantage in terms of complete Complete tumor response: tumor response, RR 1.03; 95% CI 0.95 to 1.10 FFTF or OS.

Author, year Publication Objectives Methods Results Conclusions type

Balducci RCT To evaluate the Study population: ≥65 years old Solid tumors, incidence of FN Results, con’t 200713 incidence of febrile with lung, breast, or ovarian cancer, across all cycles Arm 1: 4% neutropenia and or NHL Solid tumors, dose Arm 2: 10% reduction across all cycles related events in p=0.001 Arm 1: 7% elderly cancer Intervention: Pegfilgrastim Arm 2: 14% patients receiving beginning in cycle 1 (arm 1) versus NHL, incidence of FN across pegfilgrastim administered after all cycles NHL, dose reduction pegfilgrastim Arm 1: 15% across all cycles beginning with cycle 1 at physician's discretion Arm 2: 37% Arm 1: 16% cycle 1 (proactive) (arm 2) p=0.004 Arm 2: 8%

in comparison with Bone pain, solid tumors Solid tumors, grade 3 or 4 s.c. injection of 6 mg pegfilgrastim Arm 1: 12% pegfilgrastim neutropenia across all cycles Arm 2: 5% initiated after cycle once per cycle 24 hours after Arm 1: 30%

chemotherapy completion Arm 2: 80% 1 at the physician's Bone pain, NHL

discretion reactive). Arm 1: 9% Sample size: NHL, grade 3 or 4 Arm 2: 4% neutropenia across all cycles Arm 1: 82% Solid tumors Proactive Arm 1: 349 Arm 2: 90% pegfilgrastim use Arm 2: 352 Solid tumors, hospitalization effectively produced a across all cycles lower incidence of Arm 1: 5% NHL febrile neutropenia Arm 1: 75 Arm 2: 9% and related events in Arm 2: 76 NHL, hospitalization across all elderly patients with cycles either solid tumors or Arm 1: 17% Arm 2: 37% NHL receiving an array of mild to Solid tumors, dose delay moderately across all cycles neutropenic Arm 1: 16% Arm 2: 28% chemotherapy regimens. NHL, dose delay across all cycles Arm 1: 29% Arm 2: 23%

Author, year Publication Objectives Methods Results Conclusions type

Kuderer Meta- To assess the Adult cancer patients receiving Infection-related Prophylactic G-CSF 200714 analysis impact of primary mortality Controls: 2.8% reduces the risk of FN prophylaxis with conventional-dose chemotherapy G-CSF: 1.5% and early deaths, granulocyte colony- for solid tumors or malignant RR=0.55, 95% CI, 0.34 including infection- stimulating factor lymphoma and randomly assigned to 0.90 related mortality, on febrile to primary G-CSF prophylaxis while increasing RDI neutropenia and versus a placebo or untreated FN and musculoskeletal mortality in adult control group Controls: 39.5% pain. There are cancer patients G-CSF: 22.4% insufficient data to 17 RCTs with a total of 3,493 receiving RR=0.54, 95% CI 0.43 assess the impact of patients. chemotherapy to 0.67 G-CSF on disease- free and overall Early mortality survival Control: 5.7% G-CSF: 3.4% RR=0.60, 95% CI 0.43 to 0.83

Average RDI Controls: 86.7% G-CSF: 95.1%

Average difference in RDI between study arms: 8.4% (p=0.001)

Bone and musculoskeletal pain Controls: 10.4% G-CSF: 19.6% RR=4.02, 95% CI 2.16 to 7.52

Author, year Publication Objectives Methods Results Conclusions type

Sung 200715 Meta- To evaluate the Searched through 2006 or 2007 Infection-related Prophylactic CSFs analysis benefits of mortality may have little or no prophylactic Selected 148 trials that were CSF: 3.1% effect on mortality but hematopoietic reported in any language that Placebo/no treatment: do decrease rates of CSFs in adults and randomly assigned patients to 3.8% infection in patients children receiving CSFs or to either placebo or no RR=0.82, 95% CI 0.66 receiving cancer cancer therapy. Prophylactic CSFs were to 1.02 chemotherapy or chemotherapy or given concurrently with or after those undergoing undergoing stem- initiation of chemotherapy. Documented infections SCT. cell transplantation CSF: 38.9%

(SCT) Placebo/no treatment: 43.1% RR=0.85, 95% CI 0.79- 0.92

FN CSF: 25.3% Placebo/no treatment: 44.2% RR=0.71, 95% CI 0.63 to 0.80

Short-term all-cause mortality CSF: 7.6% Placebo/no treatment: 8.0% RR=0.95, 95% CI 0.84 to 1.08

No interactions by age or population diagnosis group and CSF effect

Author, year Publication Objectives Methods Results Conclusions type

Papaldo RCT To assess the Study population: stage I or stage Grade 2 or worse Suggests that a G- 200616 effects of G-CSF II female breast cancer patients anemia CSF dose-related on hemoglobin (Hb) EC with G-CSF: 38.8% effect may play a role value in early Intervention: EC with G-CSF. EC without G-CSF: in worsening anemia breast cancer EC: high-dose epirubicin and 26.2% in patients receiving patients receiving cyclophosphamide (120 mg/m2 p=0.005 adjuvant EC. high-dose and 600 mg/m2, respectively) on epirubicin and day 1 every 21 days. No statistically cyclophosphamide significant difference in (EC) adjuvant G-CSF given in one of five platelet count was treatment. schedules: observed between G- (1) 480 mcg sc days 8 to 14; (2) CSF and control arms. 480 mcg days 8, 10, 12, 14; (3) 300 mcg days 8 to 14; (4) 300 mcg days 8, 10, 12, and 14; and (5) 300 mcg days 8 and 12

Sample size: 506

Clinical Question 2, Secondary Prophylaxis Author, year Publication Objectives Methods Results Conclusions type

1 NCCN 2014 Guideline To provide Primarily addresses adult patients If the patient guidelines on the with solid tumors and non-myeloid experienced a use of myeloid malignancies previous episode of growth factors. FN or a dose- limiting neutropenic event, and the same chemo dose and schedule is planned for the current cycle, the patient is now in the high-risk group.

Clinical Question 3, Therapeutic CSF Author, year Publication Objectives Methods Results Conclusions type

Mhaskar Meta- To evaluate the Searched to March 2014 for Overall mortality: The use of a CSF 201417 analysis safety and efficacy randomized controlled trials (RCTs) HR=0.74, 95% CI 0.47 plus antibiotics in of adding G-CSF or that compared CSF plus antibiotics to 1.16 individuals with GM-CSF to versus antibiotics alone for the chemotherapy- standard treatment treatment of chemotherapy-induced Infection-related induced febrile (antibiotics) when febrile neutropenia in adults and mortality: neutropenia had no treating children. HR 0.75, 95% CI 0.47 effect on overall chemotherapy- to 1.20 mortality, but reduced induced febrile Included 14 RCTs (15 comparisons) the amount of time neutropenia in including a total of 1553 Hospitalized for more participants spent in individuals participants. than 10 days hospital and improved diagnosed with RR=0.65, 95% CI 0.44 their ability to achieve

cancer. to 0.95 neutrophil recovery. It

was not clear whether Duration of neutropenia CSF plus antibiotics Standardized mean had an effect on difference (SMD)= infection-related -1.70, 95% CI -2.65 to mortality. Participants -0.76 receiving CSFs had shorter duration of neutropenia, faster recovery from fever and shorter duration of antibiotics use.

Author, year Publication Objectives Methods Results Conclusions type

1 NCCN 2014 Guideline To provide Primarily addresses adult patients If previous guidelines on the with solid tumors and non-myeloid prophylaxis with use of myeloid malignancies filgrastim or growth factors. sargramostim, continue. If previous prophylaxis with pegfilgrastim, do not treat with additional CSF. Only filgrastim or sargramostim should be administered in the therapeutic setting. If no previous prophylaxis, assess risk of poor outcome. Consider CSF if high risk.

Clinical Question 4, Dose-Dense Author, year Publication Objectives Methods Results Conclusions type

Budd 201418 RCT To determine the Study population: male and Log-rank test comparing all four Patients achieved a optimal dose and female patients with high-risk arms simultaneously similar DFS with any DFS: p=0.11 schedule of pathologic stage I to III breast OS: p=0.04 of these regimens. anthracycline and cancer Subset analysis taxane DFS hazard ratios (relative to Arm suggests the administration as Interventions: 1) hypothesis that once- adjuvant therapy for Arm 2: 1.32 (95% CI 1.04 to 1.68) every-2-weeks dosing Arm 1: AC Q2 week x 6, Paclitaxel Arm 3: 1.24 (95% CI 0.98 to 1.59) early-stage breast Q2 week × 6 Arm 4: 1.12 (95% CI 0.87 to 1.44) may be best for cancer Arm 2: AC weekly x 15, Paclitaxel patients with hormone Q2 week × 6 OS hazard ratios (Arm 1 is receptor– reference group) negative/HER2- Arm 3: AC Q2 week x 6, Paclitaxel Arm 2: 1.44 (95% CI 1.08 to 1.93) weekly × 12 Arm 3: 1.46 (95% CI 1.09 to 1.95) negative tumors. Arm 4: AC weekly x 15, Paclitaxel Arm 4: 1.24 (95% CI 0.91 to 1.68) weekly × 12 Additional toxicity Toxicity was greater for results: doxorubicin-cyclophosphamide AC: doxorubicin-cyclophosphamide once every 2 weeks with regard to Grade 3 to 4 hemoglobin and leukocytes. leukopenia and Toxicity was higher for doxorubicin- neutropenia were Sample size: 2716 randomly cyclophosphamide with filgrastim observed more assigned in the original design. for mucositis and dermatologic toxicity. commonly in patients treated with More patients in the arms receiving once-per-week doxorubicin-cyclophosphamide paclitaxel, although with filgrastim (11.0%) stopped the rate of neutropenic doxorubicin-cyclophosphamide treatment early because of toxicity fever did not differ compared with those randomly between the two assigned to the arms receiving schedules. Grade 3 to doxorubicin-cyclophosphamide 4 allergic reactions, once every 2 weeks(7.9%; P = 0.006). musculoskeletal pain, and neurologic toxicity were more commonly observed in patients treated with paclitaxel once every 2 weeks.

Author, year Publication Objectives Methods Results Conclusions type

Choueiri Phase II To explore the Study population: Muscle- No febrile neutropenia or In patients with MIUC, 19 2014 efficacy and safety invasive urothelial cancer. Clinical treatment-related deaths neoadjuvant ddMVAC of neoadjuvant stage T2-T4a and <=N1 disease was well tolerated and dose-dense on imaging. 95% completed all four resulted in significant cycles of chemotherapy. methotrexate, pathologic and

vinblastine, Intervention: All patients treated radiologic Pathologic response (PaR): doxorubicin, and with ddMVAC with G-CSF support downstaging. 49% cisplatin (ddMVAC) 2 weeks per cycle with double the

with pegfilgrastim dose-intensity of cisplatin and Patients who achieved PaR support in muscle- doxorubicin, while reducing the had a 1-year DFS of 89% invasive urothelial dose of methotrexate and compared with 67% for cancer (MIUC). vinblastine by one third those patients who did not achieve PaR Sample size: 39 patients

1 NCCN 2014 Guideline To provide Primarily addresses adult patients Pegfilgrastim: there guidelines on the with solid tumors and non-myeloid are phase II studies use of myeloid malignancies that demonstrate growth factors. efficacy for chemotherapy regimens given every two weeks. Insufficient data for weekly chemotherapy regimens.

Author, year Publication Objectives Methods Results Conclusions type

Hertzberg RCT To assess the Study population: Patients aged FN In the treatment of 20 2014 effects of increasing at least 16 years with previously i-CEOP: 70% aggressive NHL in the dose intensity of untreated histologically confirmed s-CEOP: 26% pre-rituximab era, chemotherapy for aggressive NHL increasing DI did not CR or unconfirmed CR patients with result in improved i-CEOP: 53% aggressive NHL Intervention: outcomes, while at the s-CEOP: 59% same time lead to High-dose CEOP (i-CEOP) p=0.64 increased toxicity. 6 cycles, 3-weekly. cyclophosphamide 1,500, 5-yr OS epirubicin 150, vincristine 1.4 i-CEOP: 56.7% 2 mg/m all on day 1, and s-CEOP: 55.1% prednisolone 100 mg days 1-5. p=0.80 Filgrastim 5 mcg/kg/day sc, starting 9 on day 2, until ANC >10 X 10 /L to 5-yr PFS a maximum of 14 days. i-CEOP: 41% Vs s-CEOP: 43% Standard-dose CEOP (s-CEOP) p=0.73 6 cycles, 3-weekly. cyclophosphamide 750, epirubicin Differences in OS, PFS, and 75, vincristine 1.4 mg/m2 all on day TTP at 10 years were also 1, And prednisolone 100 mg days not statistically significant. 1-5. Filgrastim was permitted following i-CEOP group had a greater an episode of febrile neutropenia number of hospital inpatient or in the event of neutropenia by days, lower quality of life, Day 22. and higher rates of several AEs.

Sample size: 250

Author, year Publication Objectives Methods Results Conclusions type

Cunningham RCT To assess whether Study population: aged 18 years Grade 3 or 4 neutropenia R-CHOP-14 is not 21 2013 a benefit of dose and older with previously R-CHOP-14: 31% superior to R-CHOP- intensification with untreated, histologically confirmed, R-CHOP-21: 60% 21 chemotherapy for CHOP every 2 diffuse large B-cell lymphoma p<0.0001 previously untreated weeks is apparent according to the WHO diffuse large B-cell in the presence of classification. Patients were Grade 3 or 4 FN lymphoma; therefore, rituximab (R-CHOP) required to have Ann Arbor bulky R-CHOP-14: 5% R-CHOP-21 remains in all age groups stage IA (tumor mass diameter >10 R-CHOP-21: 11% the standard first-line cm) or stage IB to IV disease. p=0.0007 treatment in patients with this hematological 2-yr OS Intervention: malignancy. No R-CHOP-14: 82.7% molecular or clinical R-CHOP-14 (with G-CSF). R-CHOP-21: 80.8% subgroup benefited The recombinant human G-CSF HR 0.90, 95% CI 0.70-1.15 from dose lenograstim was administered on intensification in this days 4 to 12 of each cycle. 2-yr PFS study. Vs R-CHOP-14: 75.4% R-CHOP-21 (with G-CSF at R-CHOP-21: 74.8% discretion of investigator) HR 0.94, 95% CI 0.76-1.17

Sample size: Grade 3 or 4 thrombocytopenia R-CHOP-14 : 540 R-CHOP-14: 9% R-CHOP-21 : 540 R-CHOP-21: 5%

p=0.01

Frequencies of nonhematological AEs were similar in the two groups.

Author, year Publication Objectives Methods Results Conclusions type

Delarue RCT To ascertain if a Study population: Aged 60-80 Grade 3-4 neutropenia In elderly patients with 22 R-CHOP-14: 74% 2013 dose-dense R- years with untreated diffuse large untreated diffuse large R-CHOP-21: 64% CHOP regimen B-cell lymphoma and at least one B-cell lymphoma and administered every adverse prognostic factor 3-yr EFS at least one adverse 2 weeks (R- R-CHOP-14: 56% prognostic factor, a 2- CHOP14) was R-CHOP-21: 60% week dose-dense R- Intervention: HR 1.04, 95% CI 0.82-1.31 superior to the CHOP regimen did not R-CHOP-14 (G-CSF decision standard 3-week 3-yr OS improve efficacy made by treating doctor) schedule (R- R-CHOP-14: 69% compared with the 3- R-CHOP-21 (G-CSF decision CHOP21). R-CHOP-21: 72% week standard made by treating doctor) HR 0.96, 95% CI 0.73-1.26 schedule. The

In individuals who frequency of toxic Sample size: received eight planned treatment side-effects was R-CHOP-14 : 304 cycles : the median relative dose similar between R-CHOP-21 : 298 intensity for cyclophosphamide regimens, but R- was 88% (IQR 79 to 93) in the R- CHOP14 group and 97% CHOP14 was (93 to 99) in the R-CHOP21 group associated with (p<0.0001); for doxorubicin, increased need for median relative dose intensity was red-blood-cell 88% (78 to 94) and 96% (92 to 99), respectively (p<0.0001). transfusion

RBC transfusion R-CHOP-14: 47% R-CHOP-21: 31% p=0.0001

Platelet transfusion R-CHOP-14: 12% R-CHOP-21: 8% p=0.2156

At least one serious adverse event R-CHOP-14: 51% R-CHOP-21: 47%

Author, year Publication Objectives Methods Results Conclusions type

Lyman Meta- To provide a 59 RCTs with 61 separate RR for mortality All-cause mortality is 3 2013 analysis systematic review comparisons. reduced in patients and evidence Group 1 (same dose and receiving summary of the Considered studies of cancer schedule of chemotherapy): chemotherapy with impact of G-CSF patients receiving conventional RR=0.96, 95% CI 0.92 to primary G-CSF support on dose chemotherapy for solid 1.01 support. The greatest chemotherapydose tumors or malignant lymphoma and impact was observed intensity and overall randomized to primary G-CSF Group 2 (dose-dense in RCTs in patients mortality. support in one arm versus a control chemotherapy in one arm): receiving dose-dense group without initial G-CSF. RR=0.89, 95% CI 0.85 to schedules 0.94

Group 3 (dose-escalated chemotherapy in one arm): RR=0.92, 95% CI 0.85-0.99

Group 4 (substitution or addition of a drug in one arm): RR=0.94, 95% CI 0.89-0.99

Overall: RR=0.93, 95% CI 0.90-0.96

Author, year Publication Objectives Methods Results Conclusions type

Vriens RCT To determine Study population: Women FN With a higher 201323 whether delivering between the ages of 18 and 70, AC-T: 23% cumulative dose for neo-adjuvant adequate performance status, TAC: 9% the concurrent arm, no chemotherapy at a primary tumor size of 3 cm or more differences were higher dose in a and/or positive regional lymph pCR of the breast tumor observed between the shorter period of nodes. AC-T: 21% two treatment arms time improves TAC: 16% with respect to pCR outcome of breast Intervention: OR=1.44, 95% CI 0.67-3.10 rate. The differential cancer patients. Neoadjuvant TAC with G-CSF. toxicity profile could Six cycles of doxorubicin, pCR in axillary nodes partly be explained by cyclophosphamide, and docetaxel (among those with positive different use of at doses of 75, 500, and 50 mg/m2, node(s) at start) primary G-CSF respectively, every 3 weeks. AC-T: 32% prophylaxis. Pegfilgrastim 6 mg was TAC: 21% recommended as primary OR=1.77, 95% CI 0.74-4.25 prophylaxis. Vs 3-yr DFS Neoadjuvant AC-T. AC-T: 88% Four 3-weekly cycles of TAC:75% doxorubicin and cylophosphamide p=0.21 at a dose of 60 and 600 mg/m2, respectively, followed by four 3- 3-yr OS weekly cycles of docetaxel (100 AC-T: 94% mg/m2) TAC:78% p=0.11 Sample size: 201

Author, year Publication Objectives Methods Results Conclusions type

Gogas RCT To explore the Study population: Breast cancer, 5-year DFS: No DFS or OS benefit 201224 impact of dose pathological stage T(1-4)N(1-2)M0 74% in both study groups from the dose-dense intensity (DI) in the (p=0.78) sequential epirubicin adjuvant setting of Intervention: and paclitaxel was breast cancer. Dose-dense sequential epirubicin 5-year OS: detected when and paclitaxel (E-T-CMF). Three 86% with E-T-CMF, and compared to the 14-day cycles of epirubicin 110 85% with ET-CMF (p=0.45) concurrent mg/m(2), followed by three 14-day administration of the cycles of paclitaxel 250 mg/m(2), same drugs. No and three 14-day cycles of additional safety intensified CMF. Each cycle issues were raised supported by G-CSF days 2-10. with long-term follow- Vs. up. Concomitant epirubicin and paclitaxel (ET-CMF). Four 21-day cycles of combination of epirubicin at 83 mg/m2 and paclitaxel at 187 mg/m2 followed by three 14-day cycles of intensified CMF. G-CSF given during CMF.

Sample size: 1,121

Author, year Publication Objectives Methods Results Conclusions type

Arun 201125 RCT To compare the Study population: Histologic pCR A higher delivered pathologic complete diagnosis of breast cancer, stage Arm 1 (FAC): 9.0% dose intensity of response (pCR) rate IIA to IV (ipsilateral supraclavicular Arm 2 (FAC+G-CSF): doxorubicin with the of patients treated disease as the sole evidence of 13.1% FAC + G-CSF regimen FAC versus dose- metastatic disease), aged 16 to 75 p=0.35 did not result in a intense FAC plus G- years, with no prior chemotherapy, statistically significant CSF in the radiation therapy, or definitive Median neoadjuvant dose higher pCR rate. neoadjuvant setting surgical therapy for breast cancer intensity (mg/m2 per week) However, patients who and to compare the of doxorubicin achieved a pCR delivered dose Intervention: Arm 1: 15.56 experienced longer intensity, disease- Neoadjuvant FAC. 5-FU, 500 Arm 2: 20.39 DFS and OS times free survival and mg/m(2); doxorubicin, 50 mg/m(2); p<0.0001 overall survival cyclophosphamide, 500 mg/m(2)) times, and toxicity every 21 days for four cycles 5-yr OS between treatment Vs Arm 1: 66.3% arms in patients with Neoadjuvant, dose-intense FAC Arm 2: 66.6% breast cancer. plus G-CSF. 5-FU, 600 mg/m(2); p=0.61 doxorubicin, 60 mg/m(2); cyclophosphamide, 1,000 There were statistically mg/m(2)) plus G-CSF every 18 significantly higher rates of days for four cycles grade 3 and 4 neutropenia in the FAC arm. However, Sample size: the rates of FAC: 102 thrombocytopenia, febrile FAC+G-CSF: 100 neutropenia, and infection were higher in the FAC plus G-CSF arm. More than half of the patients in the FAC plus G-CSF arm required packed RBC transfusions, compared with 5% of patients in the FAC arm.

Author, year Publication Objectives Methods Results Conclusions type

Ellis 201126 RCT To compare Study population: Stage IIB, IIIA, pCR No significant clinical standard or IIIB disease and candidates for Arm 1: 20.7% benefit was seen for doxorubicin and neoadjuvant chemotherapy. Arm 2: 24.3% the investigational arm cyclophosphamide p=0.45 in this trial overall. versus weekly Intervention: doxorubicin and Standard neoadjuvant doxorubicin OS hazard ratio for daily oral and cyclophosphamide continuous arm versus cyclophosphamide Vs standard arm: plus granulocyte Continuous neoadjuvant 1.19, 95% CI 0.81-1.74 colony-stimulating doxorubicin and cyclophosphamide factor as (with G-CSF) The standard arm had neoadjuvant therapy greater toxicity from for inflammatory and Sample size: neutropenia and febrile locally advanced Arm 1 (standard): 186 (179 neutropenia. The breast cancer analyzed) continuous arm had more Arm 2 (continuous): 186 (177 stomatitis/pharyngitis and analyzed) hand-foot syndrome.

Author, year Publication Objectives Methods Results Conclusions type

Watanabe RCT To compare R- Study population: age 20 to 69 Grade 4 neutropenia The R-CHOP dose- 201127 CHOP-21 versus R- years; CD20+ histologically and grade 3 infections were dense strategy failed CHOP-14 for confirmed indolent B-cell NHL, more common with R- to improve PFS of untreated indolent including grades 1 to 3 FL; stage III CHOP-21. patients with untreated B-cell NHL. or IV disease; at least one indolent B-cell measurable lymphomatous lesion 3-yr PFS lymphoma. more than 1.5 cm detected by R-CHOP-21: 57% computed tomography (CT). R-CHOP-14: 58% 6-yr-PFS Intervention: R-CHOP-21: 41% R-CHOP-21 R-CHOP-14: 43% G-CSF used according to ASCO HR 0.92, 95% CI 0.68-1.25 guideline Vs 3-yr OS R-CHOP-14 (with G-CSF) R-CHOP-21: 95% G-CSF was administered daily for R-CHOP-14: 96% a period of 6 days, starting on day 6-yr-OS 8 and ending 2 days before CHOP R-CHOP-21: 87% of the subsequent cycle R-CHOP-14: 88% HR 1.15, 95% CI 0.57-2.30 Sample size: Arm 1: 149 Grade 3-4 hemoglobin Arm 2: 151 decrease was more common with R-CHOP-14 (but anemia was also more common at baseline in this group)

Author, year Publication Objectives Methods Results Conclusions type

Bonilla Meta- To assess the Randomized controlled trials that In the three trials of Dose-dense 201028 analysis efficacy and toxicity compared a dose-dense "conserved" dose-density chemotherapy results of the dose-dense chemotherapy protocol with a chemotherapy in better overall and chemotherapy standard chemotherapy schedule in OS HR=0.84, disease-free survival, approach in the neoadjuvant or adjuvant setting 95% CI 0.72 to 0.98 particularly in women nonmetastatic in adult women with breast cancer. DFS HR=0.83, with hormone breast cancer 95% CI 0.73 to 0.94 receptor-negative Total of 10 studies breast cancer. In two conserved dose- However, additional dense studies, DFS benefit data from randomized only apparent among controlled trials are women with hormone needed before dose- receptor-negative disease. dense chemotherapy can be considered as In six trials of "modified" the standard of care dose-dense chemotherapy OS HR=0.85, 95% CI 0.75 to 0.96 DFS HR=0.81, 95% CI 0.73 to 0.88

The rate of nonhematological adverse events was higher in the dose-dense chemotherapy arms.

Author, year Publication Objectives Methods Results Conclusions type

Moebus RCT To compare intense Study population: Women with 5-year EFS IDD-ETC was less well 201029 dose-dense (IDD) histologically confirmed primary IDD-ETC: 70% tolerated compared adjuvant breast cancer stages II to IIIA with EC-T: 62% with conventional chemotherapy with four or more positive axillary lymph HR=0.72, 95% CI 0.59 to chemotherapy but conventionally nodes; ages 18-65; M0; R0 0.87 significantly improved scheduled adjuvant resection of primary tumor and event-free and overall chemotherapy in axilla with a minimum of 10 axillary 5-year OS survivals in patients patients with high- nodes removed IDD-ETC: 82% with high-risk primary risk primary breast EC-T: 77% breast cancer who had cancer Intervention: HR=0.76, 95% CI 0.59 to four or more positive Intense dose-dense sequential 0.97 axillary lymph nodes. epirubicin, paclitaxel, and cyclophosphamide (IDD-ETC) every Hematologic and two weeks. Epirubicin 150 mg/m2 nonhematologic toxicities q2wX3, Paclitaxel 225 mg/m2 were more common with q2wX3, Cyclophosphamide 2500 IDD-ETC mg/2 q2wX3. Filgrastim s.c. 5 mcg/kg/day from days 3 to 10 of each cycle. Vs Conventionally scheduled epirubicin/Cyclophosphamide followed by paclitaxel every three weeks (EC-T). Epirubicin/cyclophosphamide (90/600 mg/m2 q3wX4) followed by paclitaxel (175 mg/m2 q3wX4).

Sample size: 1284 (658 to IDD- ETC and 626 to EC T). Analyzed: 641/611.

Author, year Publication Objectives Methods Results Conclusions type

Fayette RCT To assess standard Study population: 18-70 years of Objective response rate Treatment with 200930 versus dose- age, inoperable locally advanced or Standard MAID: 35% intensified MAID did intensified metastatic soft tissue sarcoma, no Intensified MAID: 38% not improve response doxorubicin, CNS metastases p=0.72 rate or survival and ifosfamide and cannot be dacarbazine (MAID) Intervention: Median EFS (weeks) recommended for in the first-line Standard MAID Standard MAID: 42 advanced or treatment of Six cycles of doxorubicin 20 Intensified MAID: 39 metastatic soft tissue metastatic and mg/m2/day, ifosfamide 2.5 g/ m2/day p=0.79 sarcoma. locally advanced with mesna 2.5 g/ m2/day, and soft tissue sarcoma dacarbazine 300 mg/ m2/day from Median OS (weeks) day 1-3 every 3 weeks. Standard MAID: 76 Vs Intensified MAID: 74 Dose-intensified MAID with G-CSF p=0.75 support Five cycles of doxorubicin 25 Grade 3/4 mg/m(2)/day, ifosfamide 3 g/ thrombocytopenia and m2/day with mesna 3 g/ m2/day, and anemia were more common dacarbazine 400 mg/ m2/day from in the intensified group day 1-3 every 3 weeks. Also: lenograstim 5 mcg/kg/day s.c. on days 4-14 of each cycle or until neutrophil recovery.

Sample size: 162 (80 in standard arm and 82 in experimental arm)

Author, year Publication Objectives Methods Results Conclusions type

Heigener RCT To investigate Study population: Age 18-75 with Median OS (months) Dose-intense CE with 200931 whether dose- extensive stage small cell lung Conventional: 11.2 GM-CSF support can intensified cancer. No prior chemotherapy or Dose-intensified: 11.9 be administered safely carboplatin and radiotherapy. NS but does not prolong etoposide (CE) with overall or progression- the supplementation Intervention: Median PFS (months) free survival compared of granulocyte- Dose-intensified carboplatin plus Conventional: 6.7 with standard therapy colony-stimulating etoposide with G-CSF support. Dose-intensified: 7.4 factor (G-CSF) is Carboplatin AUC 5 on day 1 IV and NS more effective than etoposide 190 mg/m(2) days 1-3 IV conventional CE in with lenograstim 263 mcg s.c. on Complete response terms of survival days 4-13, every 21 days. Conventional: 14% with acceptable Vs Dose-intensified: 22% toxicity. Conventional carboplatin plus p=0.60 etoposide. Carboplatin AUC 5 on day 1 IV and etoposide 140 Neutropenia was mg/m(2) IV on days 1-3, every 28 significantly more frequent days in the conventional group.

Sample size: 79 (37 in Thrombocytopenia was conventional group and 42 in dose- significantly more frequent intensified group) in the dose-intensified group.

Author, year Publication Objectives Methods Results Conclusions type

Lewis RCT To assess Study population: Patients aged 5-yr OS Planned intensification 200732 intensified 40 years or less with a histologically Regimen-C: 55% of chemotherapy with Regimen-DI: 58% chemotherapy for confirmed diagnosis HR, 0.94; 95% CI 0.71 to 1.24 cisplatin and osteosarcoma of high-grade osteosarcoma in an doxorubicin increased extremity long bone. 5-yr PFS received dose Regimen-C: 39% intensity and resulted Regimen-DI: 41% Intervention: HR, 0.98; 95% CI 0.77 to 1.24 in a statistically Regimen-C significant increase in (conventional treatment with six 3-week The delivered preoperative median favorable histologic 2 cycles of cisplatin [100 mg/m by 24-hour dose intensity of cisplatin was 86% response rate, but not infusion] and doxorubicin [25 mg/m2/day by in Regimen-C and 111% in 4-hour infusion for 3 days]) Regimen-DI (as the percentage of in increased Vs that planned for the conventional progression-free or Regimen-DI regimen). Postoperative median overall survival. (intensified treatment with identical total dose intensity of cisplatin was 82% doses of cisplatin and doxorubicin, planned in Regimen-C and 110% in as six 2-week cycles supported by G-CSF) Regimen-DI (the corresponding figures for doxorubicin dose intensity were similar). Sample size: Arm 1: 250 (Regimen C) Grade 3 or 4 toxicity Arm 2: 254 (Regimen-DI) White blood cell Regimen-C: 81% Regimen-DI: 69% RR, 0.85; 95% CI 0.77 to 0.95

Neutrophil Regimen-C: 92% Regimen-DI: 76% RR, 0.83; 95% CI 0.76 to 0.89

Platelet Regimen-C: 58% Regimen-DI:77% RR, 1.33; 95% CI 1.17 to 1.52

Mucositis Regimen-C: 27% Regimen-DI:35% RR, 1.30; 95% CI 0.99 to 1.70

Author, year Publication Objectives Methods Results Conclusions type

Ray- RCT To expore the Study population: histologically 2-year OS Increasing Coquard impact of increased documented, chemotherapy-naive Arm 1: 66% cyclophosphamide 200733 dose of ovarian epithelial carcinoma. Age Arm 2: 64% dose by more than 3 cyclophosphamide 18 to 70 years, FIGO stage III or IV, p=0.7 times with filgrastim in a modified CAP initiation of chemotherapy within 4 support in the modified regimen on the weeks after initial laparotomy Median OS CAP regimen CEP disease-free Arm 1: 32.5 months induces more toxicity survival (DFS) and Intervention: Arm 2: 30 months but not better efficacy overall survival (OS) Standard CEP p=0.6 in advanced ovarian of advanced ovarian Six cycles every 3 weeks of cancer. cancer patients cyclophosphamide (C), 500 mg m(- Median PFS 2), epirubicin (E) 50 mg m(-2), and Arm 1: 15.9 months cisplatin (P) 75 mg m(-2) Arm 2: 14.8 months Vs p=0.55 Intensive CEP Six cycles every 3 weeks of E and Intensive CEP group had P at the same doses, but with (C) lower rate of grade 3 or 4 1800 mg m(-2) and filgrastim 5 mug neutropenia, but higher kg(-1) per day x 10 days rates of anemia, thrombocytopenia, and Sample size: infections. Arm 1: 85 Arm 2: 79

Author, year Publication Objectives Methods Results Conclusions type

Verdonck RCT To assess whether Study population: Previously Infection grade 3 or 4 Although there was a 200734 dose intensifications untreated aggressive NHL CHOP-21: 7% tendency in favor of I- with according to the intermediate-or I-CHOP: 26% CHOP for overall cyclophosphamide high-grade Working Formulation survival (OS), disease- 6-yr OS and doxorubicin (groups D, E, F, G, and H) and an free survival (DFS), CHOP-21: 50% might improve intermediate-risk profile according I-CHOP: 61% and event-free survival outcome in younger to the HOVON criteria. HR, 0.83; 95% CI 0.62 to 1.11 (EFS), the differences patients with were not significant. intermediate-risk Intervention: 6-yr DFS aggressive NHL. CHOP-21 CHOP-21: 49% Cyclophosphamide (750 mg/m2 I-CHOP: 55% intravenously), doxorubicin (50 mg/m2 HR, 0.76; 95% CI 0.51 to 1.15 intravenously), and vincristine (2 mg intravenously) on day

1, and prednisone (100 mg orally) given on days 1 to 5. Patients were treated every 3 weeks for 8 cycles Vs I-CHOP Cyclophosphamide (1000 mg/m2 intravenously), doxorubicin (70 mg/m2 intravenously), and vincristine (2 mg intravenously) on day 1, and prednisone (100 mg orally) given on days 1 to 5. Granulocyte colony-stimulating factor was given in the I-CHOP arm only. Patients were treated every 2 weeks for 6 cycles.

Sample size: Arm 1: 239 (CHOP-21) Arm 2: 238 (I-CHOP)

Author, year Publication Objectives Methods Results Conclusions type

Sternberg RCT To assess high- Study population: Distant OS With longer follow-up 200635 dose intensity M- mestastases or unresectable M-VAC: 14.9 months initial results have VAC and G-CSF transitional cell carcinoma of the HD-M-VAC: 15.1 months been confirmed, and versus classic M- urinary tract with no prior systemic HR=0.76, 95% CI 0.58 to shows that HD-M-VAC VAC in advanced cytotoxic or biologic treatment. 0.99 produces a borderline urothelial tract statistically significant tumors Intervention: PFS relative reduction in High-dose intensity M-VAC with G- M-VAC: 8.1 months the risk of progression CSF HD-M-VAC: 9.5 months and death compared Methotrexate: 30 mg/m2 day 1 HR=0.73, 95% CI 0.56 to to M-VAC 2 Vinblastine: 3 mg/ m day 2 0.95 Adriamycin: 30 mg/ m2 day 2 Cisplatin: 70 mg/ m2 day 2 G-CSF: days 3-7 Every 15 days CR+PR Vs M-VAC: 58% Classic M-VAC HD-M-VAC: 72% Methotrexate: 30 mg/ m2 days 1, 15, 22; p=0.016 2 Vinblastine: 3 mg/ m days 2, 15, 22; Adriamycin: 30 mg/m m2 day 2 Cisplatin: 70 mg/ m2 day 2 Every 28 days Grade 4 WBC toxicity M-VAC: 16% Sample size: HD-M-VAC: 8% 134 HD-M-VAC p<0.001 129 M-VAC Neutropenic fever M-VAC: 26% HD-M-VAC: 10% p<0.001

Grade 4 platelet toxicity M-VAC: 6% HD-M-VAC: 11% p=0.033

Clinical Question 5, Stem-cell Transplantation Author, year Publication Objectives Methods Results Conclusions type

Cesaro RCT To assess the non- Study population: 0 to 17 years of Fever of unknown Pegfilgrastim was not 36 2013 inferiority of age, affected by leukemia, origin inferior to daily pegfilgrastim versus lymphoma or solid tumor who Filgrastim:79.3% filgrastim in pediatric filgrastim in speeding underwent a first autologous PBSC Pegfilgrastim: 78.1% patients who the recovery of transplant p=0.9 underwent PBSCT polymorphonuclear cells (PMN) in Intervention: One-year survival pediatric patients Filgrastim after autologous PBSCT Filgrastim: 84% who underwent 9 or more doses of filgrastim 5 mcg/kg/day Pegfilgrastim: 75% autologous (maximum 300 mcg/day). Administered beginning from day +3 after PBSC infusion p=0.8 peripheral blood Vs stem cell transplant Pegfilgrastim after autologous (PBSCT). Time to neutrophil PBSCT engraftment single dose of pegfilgrastim 100 mcg/kg Arm 1: 10.48 days (maximun 6 mg). Administered beginning from day +3 after PBSC infusion (mean) Arm 2: 10.44 days Sample size: (mean) Filgrastim: 29 p=0.3 Pegfilgrastim: 32 Time to platelet engraftment Arm 1: 28.10 days (mean) Arm 2: 33.09 days (mean) p=0.5

Grade II-IV mucositis Filgrastim: 75.9% Pegfilgrastim: 59.4% p=0.2

Author, year Publication Objectives Methods Results Conclusions type

NCCN 20141 Guideline To provide guidelines Primarily addresses adult patients Stem cell on the use of myeloid with solid tumors and non-myeloid mobilization: G-CSF growth factors. malignancies as single-agent or as part of chemo- mobilization. Combination of plerixafor and G-CSF for selected patients with NHL or multiple myeloma. Filgrastim.

Consensus is lacking on the use of growth factors in the posttransplant setting.

Limited data suggest pegfilgrastim may be equivalent to filgrastim in these settings.

GM-CSF an option for mobilization and posttransplant.

Author, year Publication Objectives Methods Results Conclusions type

Bennett Narrative To review the use of Notes that “CSFs are 201337 review CSFs for febrile not administered after neutropenia during allogeneic stem-cell cancer therapy transplantation (filgrastim and because of increased pegfilgrastim) risks of severe graft- versus-host disease, transplantation- related death, and death from other causes.” (page 4)

Author, year Publication Objectives Methods Results Conclusions type

38 Kim 2012 Meta- To assess the effects Randomized, adults, CSF Documented infections Prophylactic G-CSF analysis of G-CSF in cancer administered prophylactically RR=0.77, reduced the risk of patients receiving 95% CI 0.68 to 0.87 documented stem cell 2000-2011 infections and time to transplantation (SCT) hematologic recovery G-CSF also reduced after high-dose 7 studies included in SCT patients with time chemotherapy cancer following to hematologic (HDCT) HDCT. The G-CSF recovery treated group also

showed a decrease in Infection-related the length of hospital mortality stay. However, there RR=1.44, 95% CI 0.24 was no difference to 8.63 between G-CSF treatment group and Episodes of fever placebo group in RR=0.85, 95% CI 0.64 regard to all-cause to 1.14 mortality, infection- related mortality, All-cause mortality grade 2-4 acute graft- RR=0.92, 95% CI versus-host-disease, 0.70-1.19 and episode of fever.

Grade 2-4 GVHD RR=0.82, 95% CI 0.58-1.16

Author, year Publication Objectives Methods Results Conclusions type

Sheppard Systematic To review RCTs of Patients >18 years undergoing Growth factor alone 201239 review stem cell mobilization peripheral blood HSC collection for after chemotherapy, strategies for autologous transplantation. Study ancestim, or autologous must have compared at least 2 plerixafor provide transplantation for mobilization strategies adequate autologous hematologic using a randomized controlled study HSC grafts for the malignancies design. majority of patients. Although some 28 articles reporting on 29 studies. strategies result in higher CD34+ cell yield, this potentially comes at the expense of increased toxicity. As all strategies are reasonable, programmatic, and patient-specific considerations must inform the approach to autologous graft mobilization.

Author, year Publication Objectives Methods Results Conclusions type

Orciuolo RCT To show a lower Study population: Age 18-70 Patients with febrile Lenograstim group 40 2011 incidence of febrile years; diagnosis of multiple and episodes presented a episodes in multiple scheduled Filgrastim: 9.1% significantly higher myeloma patients to receive high-dose chemotherapy. Lenograstim: 1.1% absolute CD34+ cell receiving lenograstim p=0.03 number compared vs. filgrastim after Intervention: with the filgrastim high-dose Filgrastim after high-dose Overall, 10.8% of group but no cyclophosphamide cyclophosphamide for stem cell patients experienced at differences were for stem cell mobilization. least one adverse detected for collection mobilization vs event (any grade), efficacy. The study Lenograstim after high-dose 12.5% (11/88) in the demonstrated a lower cyclophosphamide for stem cell lenograstim and 9.1% incidence of febrile mobilization (8/88) in the filgrastim episodes with group (p = ns). lenograstim Administration of the assigned rHu compared to G-CSF started on day 4 until day 7 filgrastim. at a dosage of 30 MU/day, which was increased to 60 MU/day from day 8 until the end of aphaeresis

Sample size: 176 evaluable

Author, year Publication Objectives Methods Results Conclusions type

Gerds RCT To assess Study population: Adults Median time to This phase III study 201041 pegfilgrastim versus undergoing APBSCT for multiple neutrophil engraftment: failed to demonstrate filgrastim after myeloma, lymphoma, testicular 12 days in both groups a difference in time to autologus peripheral cancer, or ovarian cancer. neutrophil blood stem cell Adequate CD34+ cells collected for Reached the cytokine engraftment or any transplantation transplant. discontinuation clinical sequelae (APBSCT) engraftment endpoint of between pegfilgrastim Intervention: ANC 5 X 109/L X 3 days and filgrastim when Filgrastim after APBSCT or 10 X 109/L X 1 day: given post-APBSCT, Filgrastim given daily, s.c., 5 mcg/kg, from Filgrastim: 95% with pegfilgrastim day +1 until sustained engraftment or Pegfilgrastim: 44% achieving a cost through day +25 posttransplant savings over Vs Secondary outcomes that filgrastim. Pegfilgrastim after APBSCT were similar in two groups: Pegfilgrastim given as single 6 mg s.c. platelet engraftment, platelet injection on day +1 posttransplant transfusions, positive cultures for bacterial pathogens, days Sample size: 78 (39 in each arm) of fever, deaths prior to engraftment, duration of hospital stay

Author, year Publication Objectives Methods Results Conclusions type

Castagna RCT To demonstrate the Study population: Age >18; Duration of neutropenia Pegfilgrastim is not 201042 noninferiority of Hematological malignancy or solid Filgrastim: 5.97 days inferior to filgrastim in pegfilgrastim tumor; adequate harvest of CD34- Pegfilgrastim:6.20 days hematological compared with positive cells. Mean difference 0.23, reconstitution and filgrastim after high- 95% CI -0.77 to 1.22 represents an dose chemotherapy Intervention: effective alternative (HDC) and peripheral Pegfilgrastim: Mean time to reach an after HDC and PBSC. blood stem cell a single, s.c. fixed dose (6 mg) was ANC of >0.5 X 10(9)/l (PBSC) support administered 24 h after autologous PBSC Filgrastim: 11.53 infusion (day +1). Vs Pegfilgrastim: 10.75 Filgrastim: Mean difference -0.78, s.c. weight-based daily dose (5 mcg/kg/day) 95% CI -2.97 to 1.42 was administered from day +1 until ANC recovery to >0.5 X 10(9)/l for two Incidence of fever consecutive days. Filgrastim: 62%

Pegfilgrastim: 56% Sample size: 80 (40 in each group) p=0.65

Differences between groups in hematological and nonhematological toxicity were not statistically significant.

Author, year Publication Objectives Methods Results Conclusions type

DiPersio RCT To evaluate the Study population: Between 18 and Collected ≥5 X 106 Plerixafor and G-CSF 200943 safety and efficacy of 78 years old with biopsy-confirmed CD34+ cells/kg in ≤4 were well tolerated plerixafor in diagnosis of NHL, in first or second apheresis days and resulted in a mobilizing complete or partial remission, G-CSF plus plerixafor: significantly higher hematopoietic stem eligible for autologous HSCT, ≥4 59.3% proportion of patients cells for autologous weeks since last cycle of G-CSF plus placebo: with non-Hodgkin's stem-cell chemotherapy. 19.6% lymphoma achieving transplantation in p<0.001 the optimal CD34+ non-Hodgkin's Intervention: cell target for lymphoma (NHL) G-CSF plus plerixafor Underwent transplantation in patients vs transplantation after fewer apheresis days, G-CSF plus placebo initial mobilization compared with G- G-CSF plus plerixafor: CSF alone Patients received G-CSF (10 mcg/kg) 90% subcutaneously daily for up to 8 days. G-CSF plus placebo: Beginning on evening of day 4 and continuing daily for up to 4 days, patients 55.4% received either plerixafor (240 mcg/kg) or p<0.001 placebo subcutaneously. Starting on day 5, patients began daily apheresis for up to 4 Median time to days or until ≥5 x 106 CD34+ cells/kg were collected engraftment was similar in both groups. Sample size: 298 total G-CSF plus plerixafor: 150 The most common G-CSF plus placebo: 148 plerixafor-associated adverse events were GI disorders and injection site reactions.

Author, year Publication Objectives Methods Results Conclusions type

DiPersio RCT To evaluate the Study population: Between the Percentage of patients Plerixafor and G-CSF 200944 safety and efficacy of ages of 18 and 78 years with who collected ≥ 6 x 106 were well tolerated, plerixafor with G-CSF biopsy-confirmed diagnosis of CD34+ cells/kg in ≤2 and significantly more in mobilizing multiple myeloma before the first aphereses patients collected the hematopoietic stem mobilization, in first or second optimal CD34(+) cells in patients with complete or partial remission, and Plerixafor: 71.6% cell/kg target for multiple myeloma eligible for autologous Placebo: 34.4% transplantation earlier hematopoietic stem cell p<0.001 compared with G- transplantation CSF alone

Intervention: G-CSF plus plerixafor vs G-CSF plus placebo

G-CSF 10 mcg/kg per day s.c. daily for up to 8 days. Beginning on day 4, patients received either plerixafor 0.24 mg/kg or placebo s.c. daily for up to 4 days or until ≥ 6 x 106 CD34+ cells/kg were collected.

Sample size: 302 (148 plerixafor, 154 placebo)

Author, year Publication Objectives Methods Results Conclusions type

Jang 200845 RCT To compare single- Study population: Age 16 to 25 Median time to Administration of versus split-dose with multiple myeloma or NHL. neutrophil engraftment split doses of lenograstim to Scheduled for autologous SCT for ANC >0.5 X 10(9)/L lenograstim is not enhance engraftment symptomatic MM or NHL at (days) associated with after autologous chemotherapy-sensitive first relapse Single dose: 10 superior clinical stem cell or in the first partial response. Split dose: 10 efficacy compared transplantation in p=0.243 patients with multiple Intervention: with conventional myeloma or non- Single-dose lenograstim Median time to platelet daily single-dose Hodgkin's lymphoma 5 mcg/kg/day, started one day after engraftment PLT count administration for peripheral blood progenitor cell infusion and >20 X 10(9)/L (days) immediate continued until an ANC of at least 1.0 X 109/L Single dose: 11 hematopoietic Vs Split dose: 14 recovery after Split-dose lenograstim p=0.009 ASCT 2.5 mcg/kg twice a day, started one day after peripheral blood progenitor cell infusion and Duration of continued until an ANC of at least 1.0 X 109/L hospitalization (days) Single dose: 18 Sample size: 40 (21 to single-dose Split dose: 22 and 19 to split-dose) p=0.02

Author, year Publication Objectives Methods Results Conclusions type

Sung 200715 Meta- To evaluate the Searched through 2006 or 2007 Infection-related Prophylactic CSFs analysis benefits of mortality may have little or no prophylactic Selected 148 trials that were CSF: 3.1% effect on mortality but hematopoietic CSFs reported in any language that Placebo/no treatment: do decrease rates of in adults and children randomly assigned patients to 3.8% infection in patients receiving cancer CSFs or to either placebo or no RR=0.82, 95% CI 0.66 receiving cancer chemotherapy or therapy. Prophylactic CSFs were to 1.02 chemotherapy or undergoing stem-cell given concurrently with or after those undergoing transplantation (SCT) initiation of chemotherapy. Documented infections SCT. CSF: 38.9% Placebo/no treatment: 43.1% RR=0.85, 95% CI 0.79- 0.92

FN CSF: 25.3% Placebo/no treatment: 44.2% RR=0.71, 95% CI 0.63 to 0.80

Short-term all-cause mortality CSF: 7.6% Placebo/no treatment: 8.0% RR=0.95, 95% CI 0.84 to 1.08

No interactions by age or population diagnosis group and CSF effect

Author, year Publication Objectives Methods Results Conclusions type

Martino RCT To compare Study population: de novo Duration of grade 4 Pegfilgrastim can be 200646 pegfilgrastim vs. diagnosis of multiple myeloma, neutropenia (days) used with safety and filgrastim after high- stages II-III Durie Salmon Pegfilgrastim: 5 efficacy similar to dose melphalan and classification Filgrastim: 6 those provided by autologous p=NS daily injections of peripheral blood Intervention: filgrastim, and is stem cell Pegfilgrastim on day +1 after stem Incidence of FN associated with a transplantation cell infusion. Single s.c. injection, 6 Pegfilgrastim: 61.1% decreased incidence (APBSCT) in multiple mg. Filgrastim: 100% of infectious events myeloma (MM) Vs p=0.003 after APBSCT in MM patients Filgrastim starting on day +5 after patients stem cell infusion and continuing Duration of FN (days) until neutrophil engraftment. Pegfilgrastim: 1.5 5 mcg/kg/day Filgrastim: 4 p=0.005 Sample size: 37 (18 in pegfilgrastim group and 19 in Time to platelet engraftment, filgrastim group) number of red blood cell or platelet transfusions, and days of hospitalization were similar in the two study groups.

Incidence of bone pain Pegfilgrastim: 10% Filgrastim: 12% p=NS

Author, year Publication Objectives Methods Results Conclusions type

Dekker Meta- To determine Randomization between CSFs and CSF vs placebo/no CSFs were 200647 analysis whether prophylactic placebo/no therapy; CSFs given therapy associated with a CSFs after after SCT and before recovery of small reduction in the hematopoietic neutrophils; SCT conditioning Risk of documented risk of documented autologous and regimen and GVHD prophylaxis infections infections but did not allogeneic stem-cell were not planned to be different RR=0.87, 95% CI 0.76- affect infection or transplantation (SCT) between study arms 1.00 treatment-related reduced documented mortality infections 34 studies were included in the Infection-related meta-analysis. Total of 2,669 mortality (autologous participants. SCT) RR=1.09, 95% CI 0.44- 2.67

Infection-related mortality (allogeneic SCT) RR=0.37, 95% CI 0.13 to 1.05

Infection-related mortality RR=0.76, 95% CI 0.41 to 1.44

Grade 2 to 4 acute GVHD RR=1.03, 95% CI 0.81 to 1.31

Treatment-related mortality RR=1.00, 95% CI 0.78 to 1.29

Clinical Question 6, Acute leukemia, MDS

No evidence table; question not addressed by panel.

Clinical Question 7, Concomitant Chemotherapy and Radiation Therapy Author, year Publication Objectives Methods Results Conclusions type

NCCN 20141 Guideline To provide Primarily addresses adult patients Prophylactic CSFs in guidelines on the with solid tumors and non-myeloid patients given use of myeloid malignancies concurrent growth factors. chemotherapy and radiation therapy has not been evaluated and is therefore not recommended.

Clinical Question 8, Older Adults Author, year Publication Objectives Methods Results Conclusions type

Delarue RCT To ascertain if a Study population: Aged 60-80 Grade 3-4 neutropenia In elderly patients 22 R-CHOP-14: 74% 2013 dose-dense R- years with untreated diffuse large with untreated diffuse R-CHOP-21: 64% CHOP regimen B-cell lymphoma and at least one large B-cell administered every adverse prognostic factor 3-yr EFS lymphoma and at 2 weeks (R- R-CHOP-14: 56% least one adverse CHOP14) was R-CHOP-21: 60% prognostic factor, a 2- Intervention: HR 1.04, 95% CI 0.82-1.31 superior to the week dose-dense R- R-CHOP-14 (G-CSF decision standard 3-week CHOP regimen did made by treating doctor) 3-yr OS schedule (R- R-CHOP-14: 69% not improve efficacy R-CHOP-21 (G-CSF decision CHOP21). R-CHOP-21: 72% compared with the 3- made by treating doctor) HR 0.96, 95% CI 0.73-1.26 week standard

schedule. The Sample size: In individuals who received eight planned treatment cycles : the median frequency of toxic R-CHOP-14 : 304 relative dose intensity for side-effects was R-CHOP-21 : 298 cyclophosphamide was 88% (IQR 79 similar between to 93) in the R-CHOP14 group and 97% (93 to 99) in the R-CHOP21 regimens, but R- group (p<0.0001); for doxorubicin, CHOP14 was median relative dose intensity was associated with 88% (78 to 94) and 96% (92 to 99), increased need for respectively (p<0.0001). red-blood-cell RBC transfusion transfusion R-CHOP-14: 47% R-CHOP-21: 31% p=0.0001

Platelet transfusion R-CHOP-14: 12% R-CHOP-21: 8% p=0.2156

At least one serious adverse event R-CHOP-14: 51% R-CHOP-21: 47%

Author, year Publication Objectives Methods Results Conclusions type

Balducci RCT To evaluate the Study population: ≥65 years old Solid tumors, incidence of FN across Results, con’t 200713 incidence of febrile with lung, breast, or ovarian cancer, all cycles Arm 1: 4% NHL, dose reduction neutropenia and or NHL Arm 2: 10% across all cycles related events in p=0.001 Arm 1: 16%

elderly cancer Intervention: Pegfilgrastim Arm 2: 8% NHL, incidence of FN across all cycles patients receiving beginning in cycle 1 versus Arm 1: 15% Bone pain, solid tumors pegfilgrastim pegfilgrastim administered after Arm 2: 37% Arm 1: 12% beginning with cycle 1 at physician's discretion p=0.004 Arm 2: 5%

cycle 1 (proactive) Solid tumors, grade 3 or 4 neutropenia in comparison with s.c. injection of 6 mg pegfilgrastim Bone pain, NHL across all cycles Arm 1: 9% pegfilgrastim once per cycle 24 hours after Arm 1: 30% Arm 2: 4% initiated after cycle chemotherapy completion Arm 2: 80%

1 at the physician's Proactive discretion reactive). Sample size: NHL, grade 3 or 4 neutropenia across all cycles pegfilgrastim use

Arm 1: 82% effectively produced Solid tumors Arm 2: 90% a lower incidence of Arm 1: 349 febrile neutropenia Arm 2: 352 Solid tumors, hospitalization across all cycles and related events in

Arm 1: 5% elderly patients with NHL Arm 2: 9% either solid tumors or Arm 1: 75 NHL receiving an Arm 2: 76 NHL, hospitalization across all cycles Arm 1: 17% array of mild to Arm 2: 37% moderately

Solid tumors, dose delay across all neutropenic cycles chemotherapy Arm 1: 16% regimens. Arm 2: 28%

NHL, dose delay across all cycles Arm 1: 29% Arm 2: 23%

Solid tumors, dose reduction across all cycles Arm 1: 7% Arm 2: 14%

NHL, dose reduction across all cycles 55 Arm 1: 16% Arm 2: 8%

Clinical Question 9, Kids Author, year Publication Objectives Methods Results Conclusions type

Cesaro RCT To assess the non- Study population: 0 to 17 years of Fever of unknown origin Pegfilgrastim was 36 2013 inferiority of age, affected by leukemia, Filgrastim: 79.3% not inferior to daily pegfilgrastim lymphoma or solid tumor who Pegfilgrastim: 78.1% filgrastim in versus filgrastim in underwent a first autologous PBSC p=0.9 pediatric patients speeding the transplant who underwent recovery of PBSCT One-year survival polymorphonuclear Intervention: Filgrastim: 84% cells (PMN) in Filgrastim after autologous PBSCT Pegfilgrastim: 75% pediatric patients 9 or more doses of filgrastim 5 mcg/kg/day p=0.8 who underwent (maximum 300 mcg/day). Administered beginning from day +3 after PBSC infusion autologous Vs peripheral blood Time to neutrophil Pegfilgrastim after autologous stem cell transplant engraftment PBSCT Arm 1: 10.48 days (mean) (PBSCT). single dose of pegfilgrastim 100 mcg/kg Arm 2: 10.44 days (mean) (maximun 6 mg). Administered beginning from day +3 after PBSC infusion p=0.3

Sample size: Time to platelet engraftment Filgrastim: 29 Arm 1: 28.10 days (mean) Pegfilgrastim: 32 Arm 2: 33.09 days (mean) p=0.5

Grade II-IV mucositis Filgrastim: 75.9% Pegfilgrastim: 59.4% p=0.2

Author, year Publication Objectives Methods Results Conclusions type

48 Sari 2013 RCT To compare the Study population: Pediatric Incidence of FN and There is no effectiveness, patients with solid tumors and a infection were similar with difference following toxicities and the history of FN after first course of filgrastim or lenograstim the administration cost of filgrastim chemotherapy of either and lenograstim in CD34+ levels were higher lenograstim or children. Intervention: with lenograstim. filgrastim for the Filgrastim-lenograstim crossover duration of Vs Lenograstim was more neutropenia, FEN Lenograstim-filgrastim crossover expensive or hospitalization for pediatric cancer Filgrastim 5 mcg/kg patients. For stem Lenograstim 150 mcg/m2 cell mobilization, s.c. single dose per day lenograstim was superior to G-CSF administered 24 hours after filgrastim. last day of chemotherapy as secondary prophylaxis

Sample size: 29 (15 started with filgrastim and 14 started with lenograstim)

Author, year Publication Objectives Methods Results Conclusions type

Womer RCT To test the efficacy Study population: Patients 5-year EFS For localized Ewing 49 2012 and safety of younger than 50 years with newly Arm A: 65% sarcoma, chemotherapy diagnosed localized extradural Arm B: 73% chemotherapy intensification administered every Ewing sarcoma. Arm B HR=0.74 (95% CI through interval 2 weeks is more 0.54 to 0.99) compression for effective than Intervention: All patients received Ewing’s sarcoma 14 cycles of alternating vincristine- chemotherapy 5-year OS doxorubicin-cyclophosphamide administered every Arm A: 77% (VDC) and ifosfamide-etoposide 3 weeks, with no (IE) with filgrastim. Arm B: 83% increase in toxicity. Arm B HR=0.69 (95% CI Regimen A (standard): Q3W X 2, 0.47 to 1.0) then local control, then Q3W X 5 Regimen B (intensified): Q2W X 3, then local control, then Q2W X 4

Sample size: 568 (284 in each arm)

Author, year Publication Objectives Methods Results Conclusions type

50 Fox 2009 RCT To compare the Study population: Patients ages Median duration of severe A single dose per effectiveness, <26 y with Ewing sarcoma family of neutropenia cycle of tolerance, and tumors, alveolar during first two pegfilgrastim was pharmacokinetics rhabdomyosarcoma, stage 3 or 4 chemotherapy cycles well tolerated and of a single dose of embryonal rhabdomyosarcoma, Arm 1: 5.5 may be as effective pegfilgrastim to and unresectable or metastatic Arm 2: 6.0 as daily filgrastim daily filgrastim in malignant peripheral nerve sheath p=0.76 based on the children and young tumor or synovial sarcoma duration of severe adults with Median duration of severe neutropenia and sarcomas treated Intervention: neutropenia number of episodes with dose-intensive Pegfilgrastim during second two of febrile combination 100 mcg/kg s.c. as a single dose 24 chemotherapy cycles neutropenia and chemotherapy to 36 h after completion of each Arm 1: 1.5 documented cycle of chemotherapy Arm 2: 3.75 infections after Vs p=0.11 dose-intensive Filgrastim treatment with VDC 5 mcg/kg/d s.c., daily starting 24 h Twelve of 17 patients on the and IE and continuing until the postnadir pegfilgrastim arm neutrophil count was ≥10,000/mcL experienced after each cycle of chemotherapy 18 episodes (29% of cycles) of grade 3 fever and Sample size: neutropenia requiring Arm 1: 17 hospitalization during the Arm 2: 17 first four cycles of chemotherapy compared with 15 of 17 patients and 32 episodes (47% of cycles) on the filgrastim arm

Author, year Publication Objectives Methods Results Conclusions type

Lehrnbecher RCT To investigate the Study population: Children up to Neutrophil recovery (days) Since G-CSF does 51 2007 impact of G-CSF the age of 18 with newly diagnosed after first induction not influence the on hematopoetic AML. G-CSF: 18 risk of infectious recovery and No G-CSF: 23 complications or infectious Intervention: p=0.01 outcome in children complications and G-CSF vs no G-CSF undergoing therapy on outcome in Neutrophil recovery (days) for AML, one children with de G-CSF started on day 15 after after second induction cannot advocate novo AML induction therapy. 5 mcg/kg/day G-CSF: 11 the routine use of either subcutaneously or as an No G-CSF: 16 G-CSF in this intravenous infusion. Continued p=0.001 patient group. 9 until the ANC exceeded 0.5 X 10 /L on 3 consecutive days. G-CSF did not have a statistically significant effect Sample size: on platelet recovery or 161 to G-CSF infectious complications 156 to control group G-CSF did not have a statistically significant effect on complete remission, relapse, or 5-yr EFS.

G-CSF had no statistically significant effect on incidence of oral or pharyngeal mucositis grades 3-4.

Author, year Publication Objectives Methods Results Conclusions type

Wittman Meta- To definitively Included those studies of children ≤ Incidence of FN Prophylactic CSFs 52 2006 analysis assess the impact 18 years or those ≤25 years of age with CSF: 59% significantly of prophylactic and being treated on pediatric control group: 68% decrease the CSFs on the risk of oncology cooperative group OR 0.591, 95% CI: 0.431 to incidence of FN febrile neutropenia protocols 0.810 and the durations in pediatric of severe oncology patients 16 studies were included. Incidence of documented neutropenia, infection hospitalization, and with CSF: 20% antibiotic use in control group: 25% pediatric cancer OR 0.747, 95% CI: 0.518 to patients, but they 1.079 do not significantly decrease Duration of neutropenia documented mean decrease of 3.40 infections days, 95% CI: 1.85 to 4.96

Duration of hospitalization mean decrease of 1.7 days, 95% CI: 0.9 to 2.5

Clinical Question 10, Administration and Dosing of CSFs Author, year Publication Objectives Methods Results Conclusions type

1 NCCN 2014 Guideline To provide Primarily addresses adult patients Majority of trials guidelines on the with solid tumors and non-myeloid administered use of myeloid malignancies pegfilgrastim on the growth factors. day after chemotherapy. Limited data suggest that same-day pegfilgrastim may be considered in certain circumstances.

53 Aarts 2013 RCT To assess primary Study population: Patients with Percentage of patients In patients with early granulocyte colony- breast cancer with an indication for who developed FN breast cancer at high stimulating factor every-3-weeks chemotherapy in G-CSF cycles 1-6: 10% risk for FN, continued prophylaxis during the adjuvant, neoadjuvant, or G-CSF cycles 1-2: 36% use of primary G-CSF the first two cycles advanced setting prophylaxis during all only or throughout chemotherapy cycles all chemotherapy Intervention: is of clinical relevance cycles in patients G-CSF cycles 1-6 and thus cannot be with breast cancer at Vs abandoned. risk for febrile G-CSF cycles 1-2 neutropenia Pegfilgrastim at a 6-mg fixed dose was administered 24 to 30 hours after chemotherapy administration

Sample size: G-CSF cycles 1-6: 84 G-CSF cycles 1-2: 83

Author, year Publication Objectives Methods Results Conclusions type

54 Inaba 2011 RCT To assess two Study population: Children with No statistically The higher G-CSF dosages of previously untreated AML or significant differences dosage offered no prophylactic G-CSF myelodysplastic syndrome were observed between greater benefit than after induction the 2 arms in any of the the lower dosage in chemotherapy in Intervention: endpoints measured patients who were pediatric acute G-CSF 5 mcg/kg daily with receiving intensive myeloid leukemia intensive induction therapy for AML. chemotherapy for Vs AML G-CSF 10 mcg/kg daily with intensive induction therapy for AML.

Sample size: 46

Author, year Publication Objectives Methods Results Conclusions type

55 Loibl 2011 RCT To Compare of Study population: Female Grade 4 leukopenia This study failed to pegfilgrastim on day patients biologically younger than P2: 47.1% demonstrate that 2 vs. day 4 as 65 years with histologically P4: 42% pegfilgrastim on day 4 primary prophylaxis confirmed, unilateral or bilateral p=0.39 was more efficacious of intense dose- node-positive primary breast than on day 2 with dense cancer. Incidence of infections respect to grade 4 chemotherapy in P2: 29.9% leucopenia (the patients with node- Intervention: P4: 25.4% primary endpoint), positive primary Pegfilgrastim s.c. 6 mg on day 2 p=0.40 febrile neutropenia, or breast cancer (P2) infections. Vs Febrile neutropenia Pegfilgrastim s.c. 6 mg on day 4 P2: 4.7% (P4) P4: 8.0% p=0.27 Intense dose-dense ETC (epirubicin, paclitaxel, Received all planned cyclophosphamde) chemotherapy cycles of chemotherapy in both groups P2: 93.1% p4: 90.2% Sample size: 351 (174 to day 2 arm and 177 to day 4 arm) Mean relative total dose intensity per agent: difference between groups not statistically significant

Author, year Publication Objectives Methods Results Conclusions type

Zwick RCT To study the effects Study population: Age 61-80 with Percent of Administration of 201156 (phase II) of deferring previously untreated biopsy- chemotherapy cycles pegfilgrastim on day 4 pegfilgrastim until confirmed aggressive non- with grade 3 or 4 was more effective in day 4 on the Hodgkin’s lymphoma of the B-cell leukocytopenias reducing severe reduction of type Day 2: 70% leukocytopenias and chemotherapy- Day 4: 43.3% resulted in fewer induced Intervention: P < 0.001 deaths during leukocytopenia. Pegfilgrastim s.c. 6 mg on day 2 leukocytopenia. Vs Percent of Pegfilgrastim s.c. 6 mg on day 4 chemotherapy cycles with grade 4 only With R-CHOP-14 leukocytopenias Day 2: 47% Sample size: 103 Day 4: 20.5% P < 0.001

Chemotherapy cycles with grade 3 and 4 infections Day 2: 9.4% Day 4: 6.0% P = 0.118

Chemotherapy cycles with interventional antibiotics Day 2: 30.7% Day 4: 21.9% P = 0.008

Deaths Day 2: 5 Day 4: 0 P = 0.027

Author, year Publication Objectives Methods Results Conclusions type

Burris Four To compare data on Study population: Breast cancer, Breast cancer: For patients receiving 57 2010 randomized severe (grade 4) NHL, NSCLC, ovarian cancer. Age Mean cycle-1 severe pegfilgrastim with Phase II neutropenia duration >=18. neutropenia duration chemotherapy, trials and febrile was 1.2 days (95% pegfilgrastim neutropenia Intervention: confidence limit [CL], administered 24 incidence in patients Pegfilgrastim on same day as 0.7 to 1.6) longer in the hours after receiving chemotherapy same-day compared chemotherapy chemotherapy with Vs with the next-day group completion is pegfilgrastim Pegfilgrastim 24 hours after (mean, 2.6 v 1.4 days). recommended. administered the chemotherapy Grade 4 neutropenia same day or 24 was reported hours after Sample size: Across the four among 93% of same- chemotherapy studies: 279 day patients and 78% of next-day patients.

Lymphoma: Mean cycle-1 severe neutropenia duration was 0.9 days (95% CL, 0.3 to 1.4) longer in the same-day compared with the next-day group (mean, 2.1 v 1.2 days). Grade 4 neutropenia was reported among 86% of same-day patients and 64% of next-day patients.

In both studies, the ANC profile for patients receiving same-day administration was earlier, deeper, and longer than that for patients receiving next-day administration.

Author, year Publication Objectives Methods Results Conclusions type

Skarlos Observa- To evaluate the rate Study population: Breast cancer, Febrile neutropenia Pegfilgrastim 200958 tional of febrile pathological stage T1-4, N1-2, M0. Pegfilgrastim: 13% administered as neutropenia in All were participants in two Filgrastim: 1% primary prophylaxis patients with high- randomized trials (HE10/00 and p=0.001 on the same day as risk early breast HE10/05), treated with dose-dense dose-dense cancer receiving sequential chemotherapy and G- Severe neutropenia chemotherapy is less dose-dense CSF support. Pegfilgrastim-treated Pegfilgrastim: 38% efficacious than chemotherapy and, patients were matched with Filgrastim: 32% filgrastim as primary filgrastim-treated patients. p=0.36 administered on days prophylaxis, either 2-10 of each pegfilgrastim on the Exposures of interest: Treatment delays (>2 chemotherapy cycle. same day as Pegfilgrastim same-day days) chemotherapy or vs Pegfilgrastim: 57% filgrastim on days 2- Filgrastim days 2-10. Filgrastim: 61% 10 of each cycle. p=0.65 Sample size: Total of 214 patients (107 in each group). Dose reductions Pegfilgrastim: 23% Filgrastim: 23% p=1.0

Author, year Publication Objectives Methods Results Conclusions type

Hashino RCT To assess the cost Study population: >18 years of Grade 4 leukocytopenia A low dose of 200859 benefit and clinical age with NHL treated with standard (N) lenograstim might be efficacy of low-dose combination chemotherapy. Either Filgrastim: 2 safe, effective and granulocyte colony- de novo or relapsed. Lenograstim: 3 pharmaco- stimulating factor p=0.6366 economically after standard Exposures of interest: beneficial in patients chemotherapy in 75 mcg filgrastim in first course and Grade 4 neutropenia with advanced-stage patients with non- 50 mcg (low dose) lenograstim in (N) NHL. Hodgkin's lymphoma second course Filgrastim: 6 Vs Lenograstim: 10 50 mcg lenograstim in first course p=0.2207 and 75 mcg filgrastim in second course Infection (N) Filgrastim: 2 Sample size: 47 Lenograstim: 6 p=0.1213

Author, year Publication Objectives Methods Results Conclusions type

Jang 200845 RCT To compare single- Study population: Age 16 to 25 Median time to Administration of split versus split-dose with multiple myeloma or NHL. neutrophil engraftment doses of lenograstim lenograstim to Scheduled for autologous SCT for ANC >0.5 X 10(9)/L is not associated with enhance symptomatic MM or NHL at (days) superior clinical engraftment after chemotherapy-sensitive first relapse Single dose: 10 efficacy compared autologous stem cell or in the first partial response. Split dose: 10 with conventional transplantation in p=0.243 daily single-dose patients with Intervention: administration for multiple myeloma or Single-dose lenograstim Median time to platelet immediate non-Hodgkin's 5 mcg/kg/day, started one day after engraftment PLT count hematopoietic lymphoma peripheral blood progenitor cell >20 X 10(9)/L (days) recovery after ASCT infusion and continued until an ANC Single dose: 10 of at least 1.0 X 109/L Split dose: 14 Vs p=0.009 Split-dose lenograstim 2.5 mcg/kg twice a day, started one Duration of day after peripheral blood hospitalization (days) progenitor cell infusion and Single dose: 18 continued until an ANC of at least Split dose: 22 1.0 X 109/L p=0.02

Sample size: 40 (21 to single-dose and 19 to split-dose)

Clinical Question 11, Comparative Efficacy Author, year Publication Objectives Methods Results Conclusions type

autologous mcg/day). Administered beginning peripheral blood from day +3 after PBSC infusion Time to neutrophil stem cell transplant Vs engraftment (PBSCT). Pegfilgrastim after autologous Arm 1: 10.48 days (mean) PBSCT Arm 2: 10.44 days (mean) single dose of pegfilgrastim 100 p=0.3 mcg/kg (maximun 6 mg). Administered beginning from day Time to platelet engraftment +3 after PBSC infusion Arm 1: 28.10 days (mean) Arm 2: 33.09 days (mean) Sample size: p=0.5 Filgrastim: 29 Pegfilgrastim: 32 Grade II-IV mucositis Filgrastim: 75.9% Pegfilgrastim: 59.4% p=0.2

Author, year Publication Objectives Methods Results Conclusions type

48 Sari 2013 RCT To compare the Study population: Pediatric Incidence of FN and infection There is no effectiveness, patients with solid tumors and a were similar with filgrastim or difference following toxicities and the history of FN after first course of lenograstim the administration cost of filgrastim chemotherapy of either and lenograstim in CD34+ levels were higher lenograstim or children. Intervention: with lenograstim. filgrastim for the Filgrastim-lenograstim crossover duration of Vs Lenograstim was more neutropenia, FEN Lenograstim-filgrastim crossover expensive or hospitalization for pediatric cancer Filgrastim 5 mcg/kg patients. For stem Lenograstim 150 mcg/m2 cell mobilization, s.c. single dose per day lenograstim was superior to G-CSF administered 24 hours after filgrastim. last day of chemotherapy as secondary prophylaxis

Sample size: 29 (15 started with filgrastim and 14 started with lenograstim)

Author, year Publication Objectives Methods Results Conclusions type

60 Shi 2013 RCT To compare the Study population: Diagnosis of No grade 4 neutropenia, A single efficacy and safety malignant solid tumor, cycle 1 subcutaneous of a single chemotherapy-naïve. Peg-filgrastim: 89.7% injection of subcutaneous Filgrastim: 89.5% pegylated filgrastim injection of Intervention: 100 mcg/kg pegylated filgrastim Pegfilgrastim cycle 1 and filgrastim Incidence of grade 3/4 provided adequate with daily filgrastim cycle 2 or the reverse. neutropenia, FN, and and safe neutrophil as prophylaxis for antibiotic administration support neutropenia Pegfilgrastim: single dose of 100 mcg/kg were similar in the two comparable with induced by single s.c. injection on day 3 (pegfilgrastim groups. daily subcutaneous developed by CSPC Baike Bio- commonly used injections of chemotherapy pharmaceutical) unmodified Mean time to ANC recovery regimens filgrastim 5 Filgrastim: daily s.c. injections of filgrastim 5 Pegfilgratim: 8.99 days mcg/kg/day, beginning on day 3 and Filgrastim: 9.64 days mcg/kg/day in 9 continuing until ANC at least 10.0 X 10 /l p=0.001 patients receiving after expected nadir, or for a maximum of commonly used 14 days 9 standard-dose ANC <1.0 X 10 /l mild-to-moderate Sample size: Arm 1: 16% myelosuppressive Arm 1: 173 Arm 2: 16% chemotherapy Arm 2: 164 regimens.

Author, year Publication Objectives Methods Results Conclusions type

Cooper Meta- To assessed the Assessed 20 studies of primary G- Reduction in FN incidence Primary prophylaxis 20117 analysis effectiveness of G- CSF prophylaxis with no primary G- with primary versus no with G-CSFs CSFs pegfilgrastim, CSF prophylaxis: five studies of primary G-CSF significantly filgrastim or pegfilgrastim; ten of filgrastim; and reduces FN lenograstim) in five of lenograstim. Pegfilgrastim: incidence in adults reducing FN RR 0.30, 95% CI 0.14 to 0.65 undergoing incidence in adults Five studies compared pegfilgrastim chemotherapy for undergoing with filgrastim Filgrastim: solid tumors or chemotherapy for RR 0.57, 95% 0.48 to 0.69 lymphoma. solid tumors or Pegfilgrastim lymphoma. Lenograstim: reduces FN RR 0.62, 95% CI 0.44 to 0.88 incidence to a significantly greater Pegfilgrastim vs filgrastim extent than RR 0.66, 95% CI 0.44 to 0.98 filgrastim.

Author, year Publication Objectives Methods Results Conclusions type

Orciuolo RCT To show a lower Study population: Age 18-70 Patients with febrile episodes Lenograstim group 40 2011 incidence of febrile years; diagnosis of multiple and Filgrastim: 9.1% presented a episodes in multiple scheduled Lenograstim: 1.1% significantly higher myeloma patients to receive high-dose chemotherapy. p=0.03 absolute CD34+ receiving cell number lenograstim vs. Intervention: Overall, 10.8% of patients compared with the filgrastim after high- Filgrastim after high-dose experienced at least one filgrastim group but dose cyclophosphamide for stem cell no differences were adverse event (any grade), cyclophosphamide mobilization. detected for 12.5% (11/88) for stem cell vs collection efficacy. in the lenograstim and 9.1% mobilization Lenograstim after high-dose The study (8/88) in the filgrastim group cyclophosphamide for stem cell demonstrated a (p = ns) mobilization lower incidence of febrile episodes Administration of the assigned rHu with lenograstim G-CSF started on day 4 until day 7 compared to at a dosage of 30 MU/day, which filgrastim was increased to 60 MU/day from day 8 until the end of aphaeresis

Sample size: 176 evaluable

Author, year Publication Objectives Methods Results Conclusions type

Castagna RCT To demonstrate the Study population: Age >18; Duration of neutropenia Pegfilgrastim is not 201042 noninferiority of Hematological malignancy or solid Filgrastim: 5.97 days inferior to filgrastim pegfilgrastim tumor; adequate harvest of CD34- Pegfilgrastim:6.20 days in hematological compared with positive cells. Mean difference 0.23, 95% CI reconstitution and filgrastim after high- -0.77 to 1.22 represents an dose chemotherapy Intervention: effective alternative (HDC) and Pegfilgrastim: Mean time to reach an ANC after HDC and peripheral blood a single, s.c. fixed dose (6 mg) was of >0.5 X 10(9)/l PBSC. stem cell (PBSC) administered 24 h after autologous PBSC Filgrastim: 11.53 infusion (day +1). support Vs Pegfilgrastim: 10.75 Filgrastim: Mean difference -0.78, 95% s.c. weight-based daily dose (5 mcg/kg/day) CI -2.97 to 1.42 was administered from day +1 until ANC recovery to >0.5 X 10(9)/l for two Incidence of fever consecutive days. Filgrastim: 62%

Pegfilgrastim: 56% Sample size: 80 (40 in each group) p=0.65

Differences between groups in hematological and nonhematological toxicity were not statistically significant.

Author, year Publication Objectives Methods Results Conclusions type

Gerds RCT To assess Study population: Adults Median time to neutrophil This phase III study 201041 pegfilgrastim undergoing APBSCT for multiple engraftment: 12 days in both failed to versus filgrastim myeloma, lymphoma, testicular groups demonstrate a after autologus cancer, or ovarian cancer. difference in time to peripheral blood Adequate CD34+ cells collected for Reached the cytokine neutrophil stem cell transplant. discontinuation engraftment engraftment or any transplantation endpoint of ANC 5 X 109/L X clinical sequelae Intervention: 3 days or 10 X 109/L X 1 day: between Filgrastim after APBSCT Filgrastim: 95% pegfilgrastim and Filgrastim given daily, s.c., 5 mcg/kg, from Pegfilgrastim: 44% filgrastim when day +1 until sustained engraftment or given post- through day +25 posttransplant Secondary outcomes that were APBSCT, with Vs similar in two groups: platelet pegfilgrastim Pegfilgrastim after APBSCT engraftment, platelet transfusions, Pegfilgrastim given as single 6 mg s.c. positive cultures for bacterial achieving a cost injection on day +1 posttransplant pathogens, days of fever, deaths savings over prior to engraftment, duration of filgrastim. Sample size: 78 (39 in each arm) hospital stay

Author, year Publication Objectives Methods Results Conclusions type

Engert RCT To investigate Study population: Adults with Mean duration of severe Treatment with 61 2009 XM02, in aggressive NHL who planned to neutropenia (days), cycle 1 XM02 is as comparison to receive CHOP and were XM02: 0.5 beneficial as filgrastim in terms chemotherapy naïve. Filgrastim: 0.9 filgrastim in of safety and p=0.1055 ameliorating severe efficacy in the Intervention: neutropenia and prevention of XM02 Incidence of FN, cycle 1 FN in patients with chemotherapy- Vs XM02: 11.1% NHL receiving induced Filgrastim Filgrastim: 20.7% chemotherapy. neutropenia in p=0.1232 XM02 is safe and NHL. Sample size: 92 (63 in XM02 well tolerated in the 9 group and 29 in filgrastim group. Mean ANC nadir [10 /L], doses applied in cycle 1 this study. XM02: 1.7 Filgrastim: 1.1 p=0.1531

Mean time to ANC recovery (days), cycle 1 XM02: 6.0 Filgrastim: 6.7 p=0.4939

AE profile was similar between the XM02 and filgrastim groups

Author, year Publication Objectives Methods Results Conclusions type

Engert Meta- To XM02 with Adults with high-risk stage II, III, or Incidence of FN in cycle 1 XM02 62 2009 analysis filgrastim in terms IV breast cancer, small cell or demonstrated to be of its prophylactic advanced non-small cell lung Breast cancer non-inferior to effect on the cancer, or aggressive NHL. XM02: 12.1% filgrastim regarding development of Filgrastim: 12.5% the incidence of febrile neutropenia 3 Phase III trials. Included a total of XM02 minus filgrastim= FN, irrespective of (FN) during the first 608 patients (363 in XM02 group -0.4%, 95% CI -8.3% to 7.5% the myelotoxicity of chemotherapy and 245 in filgrastim group). the chemotherapy cycle in relation to Lung cancer regimen. the myelotoxic XM02: 15.0% potency of the Filgrastim: 8.8% applied XM02 minus filgrastim= chemotherapy 6.3%, 95% CI -3.2% to regimen 14.0%

NHL XM02: 11.1% Filgrastim: 20.7% XM02 minus filgrastim= -9.6%, 95% CI -28.2% to 5.2%

Adjusted estimate, XM02 minus filgrastim= 1.7%, 95% CI -3.8% to 7.1%

Author, year Publication Objectives Methods Results Conclusions type

50 Fox 2009 RCT To compare the Study population: Patients ages Median duration of severe A single dose per effectiveness, <26 y with Ewing sarcoma family of neutropenia cycle of tolerance, and tumors, alveolar during first two chemotherapy pegfilgrastim was pharmacokinetics rhabdomyosarcoma, stage 3 or 4 cycles well tolerated and Arm 1: 5.5 of a single dose of embryonal rhabdomyosarcoma, may be as effective pegfilgrastim to Arm 2: 6.0 as daily filgrastim and unresectable or metastatic p=0.76 daily filgrastim in based on the malignant peripheral nerve sheath children and young tumor or synovial sarcoma Median duration of severe duration of severe adults with neutropenia neutropenia and sarcomas treated Intervention: during second two number of episodes with dose-intensive Pegfilgrastim chemotherapy cycles of febrile combination 100 mcg/kg s.c. as a single dose 24 to 36 h Arm 1: 1.5 neutropenia and chemotherapy after completion of each cycle of Arm 2: 3.75 documented chemotherapy p=0.11 infections after Vs dose-intensive Filgrastim Twelve of 17 patients on the treatment with VDC 5 mcg/kg/d s.c., daily starting 24 h and pegfilgrastim arm experienced continuing until the postnadir neutrophil 18 episodes (29% of cycles) and IE count was ≥10,000/mcL after each cycle of of grade 3 fever and neutropenia chemotherapy requiring hospitalization during the first four cycles of chemotherapy Sample size: compared with 15 of 17 patients and Arm 1: 17 32 episodes (47% of cycles) on the filgrastim arm Arm 2: 17

Author, year Publication Objectives Methods Results Conclusions type

Gatzemeier RCT To show that a new Study population: 18 years of age Mean duration severe XM02 63 2009 granulocyte colony- with small cell or non-small cell neutropenia, cycle 1 (days) demonstrated stimulating factor, lung cancer. Chemotherapy-naive XM02: 0.5 similar efficacy and XM02, is as safe or had received no more than one Filgrastim: 0.3 safety profile as and effective as previous chemotherapy regimen filgrastim in cycle 1. filgrastim in the Mean ANC nadir, cycle 1 treatment of Intervention: XM02: 2.1 chemotherapy- XM02 and platinum-based Filgrastim: 2.9 induced chemotherapy neutropenia in vs Mean time to ANC recovery, patients with small Filgrastim and platinum-based cycle 1 (days) cell or non-small chemotherapy XM02: 6.3 cell lung cancer Filgrastim: 4.5

Sample size: Incidence of FN, cycle 1 Arm 1: 160 XM02: 15.0% Arm 2: 80 Filgrastim: 8.8% p=0.2347

AE profile similar between XM02 and Neupogen.

Author, year Publication Objectives Methods Results Conclusions type del Giglio RCT To compare XM02, Study population: Male and Mean duration of severe XM02 was superior 64 2008 and with filgrastim female patients ≥ 18 years of age neutropenia, cycle 1 to placebo and after myelotoxic with breast cancer high risk stage XM02: 1.1 days equivalent to chemotherapy in II, III or IV, chemotherapy-naïve Filgrastim: 1.1 days filgrastim in breast cancer (BC) Placebo: 3.8 days reducing duration patients. Intervention: of severe XM02 sc for at least five days Mean ANC neutropenia after starting day after chemotherapy nadir, cycle 1 myelotoxic Vs XM02: 0.7 chemotherapy Filgrastim sc for at least five days Filgrastim: 0.7 starting day after chemotherapy Placebo: 0.2

Sample size: Mean time to ANC recovery, Arm 1: 140 (XM02) cycle 1 Arm 2: 136 (Filgrastim) XM02: 8.0 days Arm 3: 72 (placebo) Filgrastim: 7.8 days Placebo: 14.0 days

Incidence of FN, cycle 1 XM02: 12.1% Filgrastim: 12.5% Placebo: 36.1%

Immunogenicity was low in all treatment groups. Fewpatients developed binding anti-G-CSF antibodies in all treatment groups whereas no confirmed plausible neutralizing antibodies were detected.

Author, year Publication Objectives Methods Results Conclusions type

65 Pinto 2007 Meta- To obtain a pooled RCTs, including phase II and FN A single dose of analysis estimate of the phase III trials, of adults with non- Pooled RR favors pegfilgrastim effect of myeloid cancer pegfilgrastim performed better pegfilgrastim RR=0.64, than a median of compared with 5 RCTS included in the meta- 95% CI 0.43 to 0.97 10-14 days of filgrastim on analysis. Total of 617 patients. filgrastim in incidence of febrile Differences between study reducing FN rates neutropenia (FN), groups in grade IV for patients and related neutropenia and time to ANC undergoing outcomes among recovery were not myelosuppressive patients with solid statistically significant. chemotherapy. tumors and

malignant Incidence of bone pain was lymphomas similar in the two study receiving groups. myelosuppressive chemotherapy.

Author, year Publication Objectives Methods Results Conclusions type

Martino RCT To compare Study population: de novo Duration of grade 4 Pegfilgrastim can 200646 pegfilgrastim vs. diagnosis of multiple myeloma, neutropenia (days) be used with safety filgrastim after high- stages II-III Durie Salmon Pegfilgrastim: 5 and efficacy similar dose melphalan classification Filgrastim: 6 to those provided and autologous p=NS by daily injections peripheral blood Intervention: of filgrastim, and is stem cell Pegfilgrastim on day +1 after stem Incidence of FN associated with a transplantation cell infusion. Single s.c. injection, 6 Pegfilgrastim: 61.1% decreased (APBSCT) in mg. Filgrastim: 100% incidence of multiple myeloma Vs p=0.003 infectious events (MM) patients Filgrastim starting on day +5 after after APBSCT in stem cell infusion and continuing Duration of FN (days) MM patients until neutrophil engraftment. Pegfilgrastim: 1.5 5 mcg/kg/day Filgrastim: 4 p=0.005 Sample size: 37 (18 in pegfilgrastim group and 19 in Time to platelet engraftment, number filgrastim group) of red blood cell or platelet transfusions, and days of hospitalization were similar in the two study groups.

Incidence of bone pain Pegfilgrastim: 10% Filgrastim: 12% p=NS

Clinical Question 12, Radiation Injury Author, year Publication Objectives Methods Results Conclusions type

Dainiak Consensus To develop Published case series and case A strong Assessment of 201166 statement evidence-based reports of individuals with HS, recommendation was therapeutic management of the published randomized controlled made for the interventions for hematopoietic trials of relevant interventions used administration of hematopoietic syndrome resulting to treat nonirradiated individuals, granulocyte colony- syndrome in humans from exposure to reports of studies in irradiated stimulating factor or exposed to ionizing radiation animals, and prior granulocyte nontherapeutic recommendations of subject matter macrophage colony- radiation is difficult experts were selected. stimulating factor and a because of the limits weak recommendation of the evidence was made for the use of erythropoiesis- stimulating agents or hematopoietic stem cell transplantation

Data Supplement 2: Additional Evidence Tables: Quality Results for RCTs Author Adequate Sufficient Similar Blinded Validated Adequate Intent- Insignificant OVERALL Randomization Sample Groups and Follow-up to-treat Conflicts of RISK OF Size Reliable Analysis Interest BIAS Measures Aarts 201353 Yes Yes Yes No Yes Yes No Unclear Intermediate Arun 201125 Yes Yes Yes No Yes Yes No Yes Low Balducci Yes Yes Yes No Yes Yes No No Intermediate 200713 Budd 201418 Yes Yes Yes No Yes Yes No Partially Low Burris Yes No Partially Yes Yes Yes No No Intermediate 201057 Castagna Unclear Unclear Yes No Yes Unclear Yes Unclear Intermediate 201042 Cesaro Yes Yes Partially No Unclear Yes Yes Yes Intermediate 201336 Cunningham Yes Yes Yes No Yes Yes Yes Unclear Low 201321 del Giglio Yes Unclear Yes Partially Yes Yes Yes No Intermediate 200864 Delarue Yes Yes Partially No Yes Yes No Unclear Low 201322 DiPersio Yes Yes Partially Yes Yes Yes Yes No Low 2009a43 DiPersio Yes Yes Yes Yes Yes Yes Yes No Low 2009b44 Ellis 201126 Yes Yes Yes No Yes Yes No Yes Low Engert Yes Unclear Partially Partially Yes Yes Yes No Intermediate 200961 Fayette Yes No Partially No Yes Unclear No Unclear Intermediate 200930

Author Adequate Sufficient Similar Blinded Validated Adequate Intent- Insignificant OVERALL Randomization Sample Groups and Follow-up to-treat Conflicts of RISK OF Size Reliable Analysis Interest BIAS Measures Fox 200950 Yes Unclear Partially No Yes Yes No Yes Intermediate Gatzemeier Yes Unclear Yes No Yes Yes Yes No Intermediate 200963 Gerds Yes Unclear Partially Yes Yes Yes No Intermediate 201041 Gogas Yes Yes Yes No Yes Yes No Yes Low 201224 Hashino Yes No Yes Unclear Yes No No Unclear High 200859 Heigener Yes No Partially No Yes Unclear No Unclear High 200931 Hertzberg Yes Yes Partially No Yes Unclear No No Intermediate 201420 Inaba 201154 Unclear Unclear Yes Yes Yes Partially No Yes Intermediate Jang 200845 Yes Unclear No No Yes Yes Yes Unclear High Kirshner Unclear Yes Yes Yes Unclear Yes No Partially Intermediate 20124 Lehrnbecher Yes Yes Partially No Yes Yes Yes Yes Low 200751 Lewis Yes Yes Yes No Yes Yes No Unclear Low 200732 Loibl 201155 Yes Yes Yes No Yes Yes No No Intermediate Martino Yes Unclear Partially No Yes Unclear Unclear Unclear High 200646 Moebus Unclear Yes Yes No Yes Yes No No Intermediate 201029

Author Adequate Sufficient Similar Blinded Validated Adequate Intent- Insignificant OVERALL Randomization Sample Groups and Follow-up to-treat Conflicts of RISK OF Size Reliable Analysis Interest BIAS Measures Orciuolo Yes Yes Partially No Yes Yes No Yes Intermediate 201140 Papaldo Unclear Unclear Unclear Unclear Yes Yes No Unclear High 200616 Ray- Yes No Yes No Yes Yes No Unclear Intermediate Coquard 200733 Sari 201348 Unclear Unclear Yes Partially Yes Unclear Yes Yes High Shi 201360 Yes Unclear Yes No Yes Yes No No Intermediate Sternberg Yes Yes Partially No Yes Yes Yes Yes Low 200635 Verdonck Yes Yes Partially No Yes Yes No Yes Low 200734 Vriens Yes Yes Yes No Yes Yes No No Intermediate 201323 Watanabe Yes Yes Partially No Yes Yes No Unclear Intermediate 201127 Womer Yes Yes Partially No Yes Yes Yes Yes Low 201249 Zwick 201156 Partially Unclear No No Yes Yes No No High

References: 1. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Myeloid Growth Factors [v2.2014]. 2. Vehreschild JJ, Bohme A, Cornely OA, et al: Prophylaxis of infectious complications with colony-stimulating factors in adult cancer patients undergoing chemotherapy--evidence-based guidelines from the Infectious Diseases Working Party AGIHO of the German Society for Haematology and Medical Oncology (DGHO). Ann Oncol, 2014 3. Lyman GH, Dale DC, Culakova E, et al: The impact of the granulocyte colony-stimulating factor on chemotherapy dose intensity and cancer survival: a systematic review and meta-analysis of randomized controlled trials. Ann Oncol 24:2475-84, 2013 4. Kirshner JJ, Heckler CE, Janelsins MC, et al: Prevention of pegfilgrastim-induced bone pain: a phase III double-blind placebo-controlled randomized clinical trial of the university of rochester cancer center clinical community oncology program research base. J Clin Oncol 30:1974-9, 2012 5. Renner P, Milazzo S, Liu JP, et al: Primary prophylactic colony-stimulating factors for the prevention of chemotherapy-induced febrile neutropenia in breast cancer patients. Cochrane Database Syst Rev 10:CD007913, 2012 6. Aapro MS, Bohlius J, Cameron DA, 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. Eur J Cancer 47:8-32, 2011 7. Cooper KL, Madan J, Whyte S, et al: Granulocyte colony-stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta-analysis. BMC Cancer 11:404, 2011 8. Kuderer NM: Meta-analysis of randomized controlled trials of granulocyte colony-stimulating factor prophylaxis in adult cancer patients receiving chemotherapy. Cancer Treat Res 157:127-43, 2011 9. Wildiers H, Reiser M: Relative dose intensity of chemotherapy and its impact on outcomes in patients with early breast cancer or aggressive lymphoma. Crit Rev Oncol Hematol 77:221-40, 2011 10. Lyman GH, Dale DC, Wolff DA, et al: Acute myeloid leukemia or myelodysplastic syndrome in randomized controlled clinical trials of cancer chemotherapy with granulocyte colony-stimulating factor: a systematic review. J Clin Oncol 28:2914-24, 2010 11. Herbst C, Naumann F, Kruse EB, et al: Prophylactic antibiotics or G-CSF for the prevention of infections and improvement of survival in cancer patients undergoing chemotherapy. Cochrane Database Syst Rev:CD007107, 2009 12. Bohlius J, Herbst C, Reiser M, et al: Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev:CD003189, 2008 13. Balducci L, Al-Halawani H, Charu V, et al: Elderly cancer patients receiving chemotherapy benefit from first-cycle pegfilgrastim. Oncologist 12:1416-24, 2007 14. Kuderer NM, Dale DC, Crawford J, et al: Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol 25:3158-67, 2007 15. Sung L, Nathan PC, Alibhai SM, et al: Meta-analysis: effect of prophylactic hematopoietic colony-stimulating factors on mortality and outcomes of infection. Ann Intern Med 147:400-11, 2007 16. Papaldo P, Ferretti G, Di Cosimo S, et al: Does granulocyte colony-stimulating factor worsen anemia in early breast cancer patients treated with epirubicin and cyclophosphamide? J Clin Oncol 24:3048-55, 2006 17. Mhaskar R, Clark OA, Lyman G, et al: Colony-stimulating factors for chemotherapy-induced febrile neutropenia. Cochrane Database Syst Rev 10:CD003039, 2014 18. Budd GT, Barlow WE, Moore HC, et al: SWOG S0221: A Phase III Trial Comparing Chemotherapy Schedules in High-Risk Early-Stage Breast Cancer. J Clin Oncol, 2014

19. Choueiri TK, Jacobus S, Bellmunt J, et al: Neoadjuvant dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin with pegfilgrastim support in muscle-invasive urothelial cancer: pathologic, radiologic, and biomarker correlates. J Clin Oncol 32:1889-94, 2014 20. Hertzberg M, Matthews JP, Stone JM, et al: A phase III randomized trial of high-dose CEOP + filgrastim versus standard-dose CEOP in patients with non-Hodgkin lymphoma: 10-year follow-up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial. Am J Hematol 89:536-41, 2014 21. Cunningham D, Hawkes EA, Jack A, et al: Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381:1817-26, 2013 22. Delarue R, Tilly H, Mounier N, et al: Dose-dense rituximab-CHOP compared with standard rituximab-CHOP in elderly patients with diffuse large B-cell lymphoma (the LNH03-6B study): a randomised phase 3 trial. Lancet Oncol 14:525-33, 2013 23. Vriens BE, Aarts MJ, de Vries B, et al: Doxorubicin/cyclophosphamide with concurrent versus sequential docetaxel as neoadjuvant treatment in patients with breast cancer. Eur J Cancer 49:3102-10, 2013 24. Gogas H, Dafni U, Karina M, et al: Postoperative dose-dense sequential versus concomitant administration of epirubicin and paclitaxel in patients with node-positive breast cancer: 5-year results of the Hellenic Cooperative Oncology Group HE 10/00 phase III Trial. Breast Cancer Res Treat 132:609-19, 2012 25. Arun BK, Dhinghra K, Valero V, et al: Phase III randomized trial of dose intensive neoadjuvant chemotherapy with or without G-CSF in locally advanced breast cancer: long-term results. Oncologist 16:1527-34, 2011 26. Ellis GK, Barlow WE, Gralow JR, et al: Phase III comparison of standard doxorubicin and cyclophosphamide versus weekly doxorubicin and daily oral cyclophosphamide plus granulocyte colony-stimulating factor as neoadjuvant therapy for inflammatory and locally advanced breast cancer: SWOG 0012. J Clin Oncol 29:1014-21, 2011 27. Watanabe T, Tobinai K, Shibata T, et al: Phase II/III study of R-CHOP-21 versus R-CHOP-14 for untreated indolent B-cell non-Hodgkin's lymphoma: JCOG 0203 trial. J Clin Oncol 29:3990-8, 2011 28. Bonilla L, Ben-Aharon I, Vidal L, et al: Dose-dense chemotherapy in nonmetastatic breast cancer: a systematic review and meta-analysis of randomized controlled trials. J Natl Cancer Inst 102:1845-54, 2010 29. Moebus V, Jackisch C, Lueck HJ, et al: Intense dose-dense sequential chemotherapy with epirubicin, paclitaxel, and cyclophosphamide compared with conventionally scheduled chemotherapy in high-risk primary breast cancer: mature results of an AGO phase III study. J Clin Oncol 28:2874-80, 2010 30. Fayette J, Penel N, Chevreau C, et al: Phase III trial of standard versus dose-intensified doxorubicin, ifosfamide and dacarbazine (MAID) in the first-line treatment of metastatic and locally advanced soft tissue sarcoma. Invest New Drugs 27:482-9, 2009 31. Heigener DF, Manegold C, Jager E, et al: Multicenter randomized open-label phase III study comparing efficacy, safety, and tolerability of conventional carboplatin plus etoposide versus dose-intensified carboplatin plus etoposide plus lenograstim in small-cell lung cancer in "extensive disease" stage. Am J Clin Oncol 32:61-4, 2009 32. Lewis IJ, Nooij MA, Whelan J, et al: Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. J Natl Cancer Inst 99:112-28, 2007 33. Ray-Coquard I, Paraiso D, Guastalla JP, et al: Intensified dose of cyclophosphamide with G-CSF support versus standard dose combined with platinum in first-line treatment of advanced ovarian cancer a randomised study from the GINECO group. Br J Cancer 97:1200-5, 2007 34. Verdonck LF, Notenboom A, de Jong DD, et al: Intensified 12-week CHOP (I-CHOP) plus G-CSF compared with standard 24-week CHOP (CHOP-21) for patients with intermediate-risk aggressive non-Hodgkin lymphoma: a phase 3 trial of the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Blood 109:2759-66, 2007 35. Sternberg CN, de Mulder P, Schornagel JH, et al: Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours. Eur J Cancer 42:50-4, 2006

36. Cesaro S, Nesi F, Tridello G, et al: A randomized, non-inferiority study comparing efficacy and safety of a single dose of pegfilgrastim versus daily filgrastim in pediatric patients after autologous peripheral blood stem cell transplant. PLoS One 8:e53252, 2013 37. Bennett CL, Djulbegovic B, Norris LB, et al: Colony-stimulating factors for febrile neutropenia during cancer therapy. N Engl J Med 368:1131-9, 2013 38. Kim S, Baek J, Min H: Effects of prophylactic hematopoietic colony stimulating factors on stem cell transplantations: meta-analysis. Arch Pharm Res 35:2013-20, 2012 39. Sheppard D, Bredeson C, Allan D, et al: Systematic review of randomized controlled trials of hematopoietic stem cell mobilization strategies for autologous transplantation for hematologic malignancies. Biol Blood Marrow Transplant 18:1191-203, 2012 40. Orciuolo E, Buda G, Marturano E, et al: Lenograstim reduces the incidence of febrile episodes, when compared with filgrastim, in multiple myeloma patients undergoing stem cell mobilization. Leuk Res 35:899-903, 2011 41. Gerds A, Fox-Geiman M, Dawravoo K, et al: Randomized phase III trial of pegfilgrastim versus filgrastim after autologus peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 16:678-85, 2010 42. Castagna L, Bramanti S, Levis A, et al: Pegfilgrastim versus filgrastim after high-dose chemotherapy and autologous peripheral blood stem cell support. Ann Oncol 21:1482-5, 2010 43. DiPersio JF, Micallef IN, Stiff PJ, et al: Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin's lymphoma. J Clin Oncol 27:4767-73, 2009 44. DiPersio JF, Stadtmauer EA, Nademanee A, et al: Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 113:5720-6, 2009 45. Jang G, Ko OB, Kim S, et al: Prospective randomized comparative observation of single- versus split-dose lenograstim to enhance engraftment after autologous stem cell transplantation in patients with multiple myeloma or non-Hodgkin's lymphoma. Transfusion 48:640-6, 2008 46. Martino M, Pratico G, Messina G, et al: Pegfilgrastim compared with filgrastim after high-dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients. Eur J Haematol 77:410-5, 2006 47. Dekker A, Bulley S, Beyene J, et al: Meta-analysis of randomized controlled trials of prophylactic granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor after autologous and allogeneic stem cell transplantation. J Clin Oncol 24:5207-15, 2006 48. Sari N, Dalva K, Ilhan IE: Comparison of filgrastim and lenograstim in pediatric solid tumors. Pediatr Hematol Oncol 30:655-61, 2013 49. Womer RB, West DC, Krailo MD, et al: Randomized controlled trial of interval-compressed chemotherapy for the treatment of localized Ewing sarcoma: a report from the Children's Oncology Group. J Clin Oncol 30:4148-54, 2012 50. Fox E, Widemann BC, Hawkins DS, et al: Randomized trial and pharmacokinetic study of pegfilgrastim versus filgrastim after dose-intensive chemotherapy in young adults and children with sarcomas. Clin Cancer Res 15:7361-7, 2009 51. Lehrnbecher T, Zimmermann M, Reinhardt D, et al: Prophylactic human granulocyte colony-stimulating factor after induction therapy in pediatric acute myeloid leukemia. Blood 109:936-43, 2007 52. Wittman B, Horan J, Lyman GH: Prophylactic colony-stimulating factors in children receiving myelosuppressive chemotherapy: a meta-analysis of randomized controlled trials. Cancer Treat Rev 32:289-303, 2006 53. Aarts MJ, Peters FP, Mandigers CM, et al: 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. J Clin Oncol 31:4290-6, 2013 54. Inaba H, Cao X, Pounds S, et al: Randomized trial of 2 dosages of prophylactic granulocyte-colony-stimulating factor after induction chemotherapy in pediatric acute myeloid leukemia. Cancer 117:1313-20, 2011 90

55. Loibl S, Mueller V, von Minckwitz G, et al: Comparison of pegfilgrastim on day 2 vs. day 4 as primary prophylaxis of intense dose-dense chemotherapy in patients with node-positive primary breast cancer within the prospective, multi-center GAIN study: (GBG 33). Support Care Cancer 19:1789-95, 2011 56. Zwick C, Hartmann F, Zeynalova S, et al: Randomized comparison of pegfilgrastim day 4 versus day 2 for the prevention of chemotherapy- induced leukocytopenia. Ann Oncol 22:1872-7, 2011 57. Burris HA, Belani CP, Kaufman PA, et al: Pegfilgrastim on the Same Day Versus Next Day of Chemotherapy in Patients With Breast Cancer, Non- Small-Cell Lung Cancer, Ovarian Cancer, and Non-Hodgkin's Lymphoma: Results of Four Multicenter, Double-Blind, Randomized Phase II Studies. J Oncol Pract 6:133-40, 2010 58. Skarlos DV, Timotheadou E, Galani E, et al: Pegfilgrastim administered on the same day with dose-dense adjuvant chemotherapy for breast cancer is associated with a higher incidence of febrile neutropenia as compared to conventional growth factor support: matched case-control study of the Hellenic Cooperative Oncology Group. Oncology 77:107-12, 2009 59. Hashino S, Morioka M, Irie T, et al: Cost benefit and clinical efficacy of low-dose granulocyte colony-stimulating factor after standard chemotherapy in patients with non-Hodgkin's lymphoma. Int J Lab Hematol 30:292-9, 2008 60. Shi YK, Chen Q, Zhu YZ, et al: Pegylated filgrastim is comparable with filgrastim as support for commonly used chemotherapy regimens: a multicenter, randomized, crossover phase 3 study. Anticancer Drugs 24:641-7, 2013 61. Engert A, Griskevicius L, Zyuzgin Y, et al: XM02, the first granulocyte colony-stimulating factor biosimilar, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with non-Hodgkin lymphoma receiving chemotherapy. Leuk Lymphoma 50:374- 9, 2009 62. Engert A, del Giglio A, Bias P, et al: Incidence of febrile neutropenia and myelotoxicity of chemotherapy: a meta-analysis of biosimilar G-CSF studies in breast cancer, lung cancer, and non-Hodgkin's lymphoma. Onkologie 32:599-604, 2009 63. Gatzemeier U, Ciuleanu T, Dediu M, et al: XM02, the first biosimilar G-CSF, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell or non-small cell lung cancer receiving platinum-based chemotherapy. J Thorac Oncol 4:736-40, 2009 64. del Giglio A, Eniu A, Ganea-Motan D, et al: XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy. BMC Cancer 8:332, 2008 65. Pinto L, Liu Z, Doan Q, et al: Comparison of pegfilgrastim with filgrastim on febrile neutropenia, grade IV neutropenia and bone pain: a meta- analysis of randomized controlled trials. Curr Med Res Opin 23:2283-95, 2007 66. Dainiak N, Gent RN, Carr Z, et al: First global consensus for evidence-based management of the hematopoietic syndrome resulting from exposure to ionizing radiation. Disaster Med Public Health Prep 5:202-12, 2011

DATA SUPPLEMENT 3. Search Strategy String and Dates

Computerized literature searches of MEDLINE and the Cochrane Collaboration Library were performed. The searches of the English-language literature published from October 1, 2005 to September 30, 2014 combined terms for colony-stimulating factors, study designs of interest, cancer, and stem cell transplantation. Results of the database searches were supplemented with contributions from Update Committee members’ personal files.

CSF

((((((((((((( "Colony-Stimulating Factors/administration and dosage"[Mesh] OR "Colony-Stimulating Factors/adverse effects"[Mesh] OR "Colony-Stimulating Factors/therapeutic use"[Mesh] ))))) OR “colony-stimulating factor”[tiab])) NOT "Erythropoietin"[Mesh]) NOT "Thrombopoietin"[Mesh])) OR (((( "Granulocyte Colony-Stimulating Factor/administration and dosage"[Mesh] OR "Granulocyte Colony-Stimulating Factor/adverse effects"[Mesh] OR "Granulocyte Colony-Stimulating Factor/therapeutic use"[Mesh] ))))) OR ((( "Granulocyte-Macrophage Colony-Stimulating Factor/administration and dosage"[Mesh] OR "Granulocyte-Macrophage Colony-Stimulating Factor/adverse effects"[Mesh] OR "Granulocyte- Macrophage Colony-Stimulating Factor/therapeutic use"[Mesh] )))) OR ((“granulocyte colony-stimulating factor”[tiab] OR “granulocyte-macrophage colony-stimulating factor”[tiab] OR gcsf[tiab] OR “g csf”[tiab] OR gmcsf[tiab] OR “gm csf”[tiab]))) OR ((Filgrastim OR pegfilgrastim OR sargramostim OR lenograstim))

Cancer cancer[TIAB] OR neoplasms[MeSH] OR neoplasm*[TIAB] OR tumor[TIAB] OR tumors[TIAB] OR tumour[TIAB] OR tumours[TIAB] OR malignant[TIAB] OR malignancy[TIAB] OR malignancies[TIAB] OR carcinoma[TIAB] OR oncology[TIAB] OR lymphoma[TIAB] OR leukemia*[TIAB] OR *glioma*[TIAB] OR hepatocellular[TIAB] OR sarcoma[TIAB] OR myeloma[TIAB]

Stem cell transplantation

“stem cell transplantation”[MeSH] or “stem cell transplantation”[TIAB]

Randomized trial search

"Clinical Trials, Phase III as Topic"[Mesh] OR "Clinical Trial, Phase III" [Publication Type] OR "Controlled Clinical Trial" [Publication Type] OR "Randomized Controlled Trial" [Publication Type]

Combined search

CSF AND randomized trials AND (cancer OR stem-cell transplantation)

CSF AND systematic[sb]

DATA SUPPLEMENT 4. QUOROM Diagram

562 potentially relevant abstracts identified

10 papers identified through

expert consultation

84 papers selected for

full-text review

18 papers were excluded. Primary reason for exclusion:  8 not outcome of interest  10 not study design of interest

66 papers met selection criteria

Data Supplement 5: Clinical Questions 1. Among adults treated with chemotherapy for a solid tumor or lymphoma, what factors should clinicians

consider when selecting patients for primary prophylaxis of febrile neutropenia with a CSF?

2. Among adults treated with chemotherapy for a solid tumor or lymphoma, what factors should clinicians

use to select patients for secondary prophylaxis of febrile neutropenia with a CSF?

3. Are there circumstances in which CSFs should be considered for the treatment of neutropenia among

adults with cancer?

4. In what settings should CSFs be used in order to increase chemotherapy dose-density?

5. What is the role of CSFs as adjuncts to progenitor-cell transplantation?

6. What is the role of CSFs in the setting of acute leukemia or myelodysplastic syndromes?

7. Should CSFs be avoided in patients receiving concomitant chemotherapy and radiation therapy?

8. Are there CSF recommendations that apply specifically to older adults, and that differ from

recommendations in younger adults?

9. How should CSFs be used in the pediatric population?

10. What are recommendations for the initiation, duration, dosing, and administration of CSFs?

11. Do CSFs differ in efficacy?

12. What is the role of CSFs in the treatment of radiation injury?