Conditions: Neuroblastoma
Keywords: Sargramostim Cyclophosphamide Topotecan Cisplatin Dexrazoxane Doxorubicin Etoposide Filgrastim Vincristine Mesna
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 13
Healthy volunteers: no

Brief summary:
Patients will be asked to participate in this study because patients have been diagnosed with high-risk neuroblastoma, a common childhood cancer which has aggressive features. If left untreated, high-risk neuroblastoma is fatal. Children with high-risk neuroblastoma often respond to current available treatments, but there is a high risk that the cancer will return.

This study will test the safety of giving standard induction treatment for high-risk neuroblastoma without one of the drugs commonly used to prevent side effects. Current treatment for high-risk neuroblastoma includes anti-cancer drugs (chemotherapy), surgery, radiation therapy and high-dose chemotherapy with hematopoietic stem cell rescue. Treatment takes about one year to complete and occurs in 3 phases: induction, consolidation, and maintenance. This study is limited to the induction phase of treatment.

Induction therapy includes six chemotherapy drugs given in different combinations every 3 weeks for a total of 6 courses. For the past decade, induction chemotherapy has been followed by a drug called granulocyte colony stimulating factor (G-CSF, filgrastim, peg-filgrastim, Neupogen, or Neulasta) to prevent side effects from the chemotherapy. G-CSF is routinely given to patients with high risk neuroblastoma after chemotherapy to stimulate white blood cell production and shorten the time period when the absolute neutrophil count (ANC), a type of white blood cell, is low after chemotherapy. G-CSF is known to shorten the period of low ANC by approximately 3 days. When the ANC is lowest, a patient is most at risk of getting a bacterial infection.

Recent lab experiments in mice have shown that neuroblastoma tumor cells may respond to G-CSF by growing faster and metastasizing (spreading to other parts of the body). There have been no clinical trials comparing the survival of children with high risk neuroblastoma with or without G-CSF. This clinical trial is the first step towards giving induction chemotherapy with less G-CSF.

The goal of this study is to determine if it is safe to give induction chemotherapy to children with neuroblastoma without giving G-CSF routinely.

Detailed description:
Chemotherapy:

CYCLE 1+2: Topotecan and cyclophosphamide

Cycle 3+5: Cisplatin and Etoposide

Cycle 4+6: Vincristine, Cyclophosphamide and Doxorubicin

Stem cell collection: After the third cycle of chemotherapy, stem cells will be collected for possible stem cell transplantation at a later date using apheresis. In order to have enough stem cells present in the blood, the patient will need to receive daily G-CSF injections before this collection.

Surgery: After the 5th cycle of chemotherapy, most patients will have surgery to remove as much remaining tumor as possible.

Growth factor support: Growth factors to increase the number of white blood cells, G-CSF and GM-CSF(granulocyte-macrophage colony stimulating factor) will not be given routinely in this study. GM-CSF will be given for patients who have serious bacterial infections or delays in administering chemotherapy because of low neutrophil counts. All people enrolled on the study will receive GM-CSF prior to having surgical removal of the main tumor. All people enrolled on the study will also receive G-CSF prior to having patients stem cells collected.

Optional survey: This research study includes an optional survey regarding quality of life while on the study. This survey will be filled out after cycles 1 and 4 of chemotherapy.

Drug Shortages:

In the event of a drug shortage of a medication that is not a G-CSF or GM-CSF product, the provider may use best clinical judgment regarding omission of the agent or substitution with a different agent. The medical and research records of study patients should reflect that the patient was informed of any delays and/or modifications in protocol therapy related to the shortage of the agent and the associated risks.

Arms:
arm 1: Induction chemotherapy only, including 6 cycles of chemotherapy, tumor resection, and stem cell collection

Interventions: intervention 1: Topotecan intervention 2: Cyclophosphamide intervention 3: Cisplatin intervention 4: Etoposide intervention 5: Vincristine intervention 6: Cyclophosphamide intervention 7: Doxorubicin intervention 8: Sargramostim
Intervention descriptions: intervention 1: CYCLE 1+2 (given by intravenous catheter daily for 5 days) intervention 2: CYCLE 1+2 (given by intravenous catheter daily for 5 days) intervention 3: Cycle 3+5 (given daily x 4 days) intervention 4: Cycle 3+5 (given daily for 3 days) intervention 5: Cycle 4+6 (given daily for 3 days) intervention 6: Cycle 4+6 (given daily for 2 days) intervention 7: Cycle 4+6 (given daily for 3 days) intervention 8: Granulocyte macrophage colony stimulating factor (rhu GM-CSF, rGM-CSF, GM-CSF)

Protocol document:
Prot_SAP_000.pdf: 
 
PROTOCOL COVER PAGE 
 
Protocol Title:  
A Safety Pilot Study of High Risk Induction Chemotherapy for Neuroblastoma 
without Prophylactic Administration of Myeloid Growth Factors (SPRING) 
 
Version 7.0 dated 11.14.2019 
 
NCT# 02786719 
 
 


Version 1.0 (01/11/2016) 
 
Version 5.0 (07/07/2017) 
Version 1.1 (02/03/2016) 
 
Version 6.0 (02/06/2018) 
Version 1.2 (02/12/2016)                                                              Version 7.0 (11.14.2019) 
Version 1.3 (03/17/2016) 
Version 2.0 (11/21/2016 ) 
Version 3.1 (01/12/2017) 
Version 4.0 (04/05/2017) 
 
A Safety Pilot Study of High Risk Induction Chemotherapy for Neuroblastoma 
without Prophylactic Administration of Myeloid Growth Factors (SPRING) 
 
  
Principal Investigator 
Sarah Whittle, MD 
Texas Children’s Cancer and Hematology Centers 
Baylor College of Medicine 
 
 
Co-Investigators 
Jennifer Foster, MD 
Andras Heczey, MD 
Robert Krance, MD 
Heidi Russell, MD, PhD 
Jason Shohet, MD, PhD 
M. Brooke Bernhardt, PharmD 
Statistician: Charles Minard, PhD 
 
 


 
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TABLE OF CONTENTS 
1 
ABSTRACT: .................................................................................................. 3 
2 
EXPERIMENTAL DESIGN SCHEMA: ........................................................... 4 
3 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) ......................................... 5 
4 
BACKGROUND ............................................................................................. 6 
5 
ELIGIBILITY CRITERIA AND SUBJECT RECRUITMENT .......................... 16 
6 
TREATMENT PLAN .................................................................................... 19 
7 
STUDIES TO BE OBTAINED WHILE ON PROTOCOL THERAPY ............ 35 
8 
EVALUATION CRITERIA ............................................................................ 35 
9 
DRUG INFORMATION ................................................................................ 36 
10 OFF THERAPY AND OFF STUDY CRITERIA ............................................ 39 
11 SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS ........... 40 
12 DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY .. 42 
13 FINANCIAL CONSIDERATIONS ................................................................ 43 
14 POTENTIAL RISKS AND BENEFITS .......................................................... 43 
15 STATISTICAL CONSIDERATIONS ............................................................ 50 
16 ASSESSMENT OF FAMILY BURDEN ........................................................ 55 
 
 
 


 
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1 
ABSTRACT: 
Current induction chemotherapy for high risk neuroblastoma involves 6 cycles of 
chemotherapy followed by high dose chemotherapy with autologous stem cell 
rescue and then a combination of immunotherapy and differentiation therapy for 
maintenance.  Standard practice for supportive care for these patients typically 
includes adjuvant G-CSF (Granulocyte Colony Stimulating Factor) to limit 
chemotherapy related neutropenia, based on the assumption that this reduces 
risk of infection. New data from preclinical models of neuroblastoma demonstrate 
that G-CSF promotes the maintenance of neuroblastoma cancer stem cells and 
may reduce the efficacy of chemotherapy by promoting neuroblastoma 
metastasis and drug resistance and use of G-CSF could reduce the overall 
efficacy of our current treatment protocols of high-risk neuroblastoma. Prior to 
performing randomized trials to test this hypothesis, we propose to determine the 
feasibility and safety of removing prophylactic G-CSF administration from our 
supportive care practice for these patients. Thus we propose the following non-
inferiority protocol to test the safety and feasibility of this alternative supportive 
care approach to HR NB induction chemotherapy. 
 
 


 
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2 
EXPERIMENTAL DESIGN SCHEMA: 
 
 
 
 
 


 
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3 
GOALS AND OBJECTIVES (SCIENTIFIC AIMS) 
3.1 Primary Aim: 
To determine the safety and feasibility of administering induction chemotherapy 
for high risk neuroblastoma patients without routine G-CSF administration for 
supportive care.  
3.2  Secondary Aims: 
3.2.1 To determine the incidence and duration of delay in chemotherapy 
administration due prolonged neutrophil recovery in patients undergoing 
induction chemotherapy for high-risk neuroblastoma without prophylactic 
G-CSF 
3.2.2 To determine the number of antibiotic days and hospital days due to fever 
and/or infection in patients undergoing induction chemotherapy for high-
risk neuroblastoma without prophylactic G-CSF  
3.2.3 To determine the number of platelet transfusions in patients undergoing 
induction chemotherapy for high-risk neuroblastoma without prophylactic 
G-CSF 
3.2.4 To describe the response rate following induction chemotherapy without 
prophylactic G-CSF for patients with high-risk neuroblastoma 
3.2.5 To describe caregiver burden in patients undergoing induction 
chemotherapy for high risk neuroblastoma  
 
 
 


 
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4 
 BACKGROUND 
4.1 Introduction/Rationale for development: 
Neuroblastoma is the most common extracranial solid tumor of childhood 
and accounts for 15% of pediatric cancer related mortality [1].  Only 50% of 
children with aggressive, metastatic tumors (i.e. high-risk disease) achieve long 
term survival despite aggressive treatment including multi-agent chemotherapy, 
surgery, radiation therapy and biologic agents [2]. The majority of deaths from 
neuroblastoma are due to relapsed disease.  It is thought that most solid tumors, 
neuroblastoma included, are made up of heterogeneous populations of cells in 
various states of differentiation and with varying levels of tumorigenicity and 
chemosensitivity [2].  Though chemotherapy may eradicate the majority of these 
subpopulations, cancer stem cells (CSCs) are generally resistant to 
chemotherapy and their persistence may repopulate new tumors in metastatic 
sites after completion of chemotherapy, leading to relapse. CSCs have been 
described in the majority of aggressive malignancies including breast, colon, lung 
and brain tumors [3-5]. 
Recently, a novel CSC subpopulation in neuroblastoma has been 
characterized based on expression of CD114, the Granulocyte-Colony 
Stimulating Factor receptor (G-CSFR) [6]. Colony stimulating factors, including 
granulocyte-colony stimulating factor (G-CSF), are cytokines that are produced at 
low levels continuously and increase in response to several specific stimuli such 
as infection or reduction in the number of terminally differentiated hematopoietic 
cells. Recombinant human granulocyte colony-stimulating factor (r-metHuGCSF, 
filgrastim) is used extensively as an adjuvant to myelosuppressive chemotherapy 


 
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to decrease the duration of chemotherapy-induced myelosuppression. Over the 
past 10 years G-CSF was introduced into protocols for pediatric cancers based 
on data extrapolated from adults demonstrating a reduction in duration of severe 
neutropenia and reduction in risk of febrile neutropenia [7].  However, the risk 
versus benefit of routine adjuvant G-CSF has not been directly studied in 
neuroblastoma patients receiving our current regimen. 
Recent data demonstrates that G-CSF acts as a CSC-specific growth 
factor via G-CSF receptor mediated activation of the STAT3 signaling pathway, a 
signaling mechanism critical in neural crest differentiation [8].  Exogenous G-CSF 
increases metastasis and tumor growth of neuroblastoma xenografts growing in 
immunodeficient mice (Figure 1), while STAT 3 inhibition has the opposite effect. 
Importantly, G-CSF also up regulates a number of STAT3 dependent anti-
apoptotic and DNA repair mechanisms in the stem cell population.  Additionally, 
orthotopic mouse xenograft models treated with chemotherapy followed by G-
CSF had significantly larger tumors than those treated with chemotherapy alone, 
suggesting a pro-tumor effect of G-CSF (Figure 2).  Together, these results raise 
the concern that routine administration of G-CSF after chemotherapy for 
neuroblastoma may be counter-productive and enhance drug resistance and 
persistence of metastatic disease. Thus, the role of G-CSF in promoting the 
tumorigenicity of neuroblastoma CSCs mandates a re-evaluation of the risks and 
benefits of the adjuvant use of G-CSF during chemotherapy for children with high 
risk neuroblastoma.  


 
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As a first step towards a definitive trial comparing the effects of G-CSF on 
survival, we must first assess the safety and feasibility of removing prophylactic 
G-CSF from chemotherapy. This protocol is a pilot study designed to test our 
hypothesis that the risk of severe infections during induction chemotherapy 
without prophylactic G-CSF will be equivalent to historical and published data.  
The results from this protocol will be used to inform a future randomized trial.  
Figure 1. G-CSF signaling significantly promotes tumor growth in vivo:  
 
Figure 1. In vivo bioluminescence imaging of xenografts treated with G-CSF or 
neutralizing antibody to G-CSF demonstrated a marked effect of the exogenous 
cytokine promoting tumor growth. (From Agarwal et al 2015). 
 
Figure 2. Chemotherapy with and without G-CSF administration in mice: 


 
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Figure 2.  Preliminary data demonstrating G-CSF given after chemotherapy 
(topotecan and cyclophosphamide) reduces the efficacy of these drugs.  A. 
Treatment schedule for chemotherapy regimen B. Tumor weights (N=6) and C. 
CD-114 positive neuroblastoma cells in cohorts of mice treated with 
chemotherapy with or without G-CSF.  Far right: Representative imaging results 
of treatment cohorts after 3 cycles of therapy. 
 
 
 
 
 


 
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4.2 Induction Therapy 
 
 Standard chemotherapy for high-risk neuroblastoma begins with an initial 
phase of therapy aimed at inducing a remission of disease. Achievement of 
complete response following induction chemotherapy significantly impacts long-
term survival [9]. Despite modest improvements in outcomes due to significant 
chemotherapy dose intensification, durable remission rates remain low, with 15-
20% of patients progressing during induction therapy and another 40% 
progressing after an initial response to induction [10-12]. The current Children’s 
Oncology Group induction chemotherapy regimen includes anthracyclines, 
alkylators, platinum compounds, and topoisomerase II inhibitors delivered every 
21 days for 6 cycles [13].  Surgical resection of the primary tumor and bulky 
metastatic sits is usually needed to achieve a partial response by the end of 
induction therapy. Tumors frequently adhere to or invade local vital structures 
[14], resulting in significant complications including normal organ removal and 
hemorrhage [15, 16], particularly if resection is attempted before chemotherapy.  
Surgery after or near completion of induction therapy is an accepted practice and 
improves the likelihood of resection [17]. 
 
 For the 80 to 95% of children with a good response to induction, treatment 
continues with consolidation and maintenance phases.  These components of 
treatment are not part of this clinical trial, however current practice for these 
phases include radiation therapy to the primary tumor bed and residual 
metastatic sites, high-dose chemotherapy with autologous stem cell rescue, 
followed by six months of biologic and immunotherapy.  Collection of autologous 


 
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stem cells occurs during induction therapy. Best practice at Texas Children’s 
Cancer Center has been to perform this collection after induction chemotherapy 
course #3 via pharesis following stimulation of stem cell production and 
mobilization with G-CSF.  
4.3 Prophylactic Use of Colony Stimulating Factors 
The prophylactic use of myeloid colony stimulating factors (CSFs) has 
been described in two scenarios. Use of CSFs to decrease duration of 
myelosuppression after chemotherapy is referred to as primary prophylaxis, while 
an attempt to prevent febrile neutropenia or a delay in subsequent chemotherapy 
administration is called secondary prophylaxis. [18]. The American Society of 
Clinical Oncology (ASCO) has developed guidelines for the use of these 
medications based on review of the published literature, with the most recent 
update in 2015 [19]. Guidelines for use in adults recommend prophylactic use in 
patients in whom the expected incidence of febrile neutropenia is at least 20% 
and in patients who have already had an episode of febrile neutropenia.  These 
guidelines have been applied to children without conclusive evidence supporting 
their use, and certainly without evidence specific to children with high-risk 
neuroblastoma.  
While some studies have shown a reduction in rate of febrile neutropenia 
and length of hospitalization for febrile neutropenia, there has not been a 
demonstrated decrease in infection related mortality [20, 21].  A study of 
neuroblastoma patients undergoing the dose and time intensive chemotherapy 
protocol “Rapid COJEC” demonstrated similar findings with no decrease in rate 
of serious bacterial infections or mortality. This study demonstrated improvement 


 
12
in compliance with chemotherapy schedule, however, the Rapid COJEC protocol 
delivers chemotherapy on an every 10 day schedule regardless of hematologic 
count criteria, provided the patient does not have an active infection [22]. This is 
not applicable to standard North American regimens which deliver chemotherapy 
in a less time intensive manner (10 days vs. 21-29 days between cycles) 
adhering to count recovery criteria.  Furthermore, a study randomizing high risk 
neuroblastoma patients receiving dose and time intensive chemotherapy to either 
receive prophylactic G-CSF or not, found no impact of G-CSF on febrile 
episodes. This study demonstrated that patients receiving G-CSF had faster 
recovery of absolute neutrophil count, on average 3 days sooner to reach an 
absolute neutrophil count (ANC) above 500/μL.  However, subjects who received 
G-CSF had slower platelet recovery for all chemotherapy following the third 
cycle. The authors concluded that while G-CSF use hastened neutrophil 
recovery, it did not impact dose intensity due to this delay in platelet recovery 
[23]. 
The most commonly used colony stimulating factor in pediatrics is 
granulocyte colony stimulating factor (G-CSF, filgrastim). This cytokine binds the 
G-CSF receptor (AKA CD114, also found on neuroblastoma stem cells) on 
neutrophil precursors to activate STAT3 dependent expansion and lineage 
differentiation to increase neutrophil counts in response to inflammatory stress. A 
commonly used formulation is peg-filgrastim, a pegylated form of G-CSF allowing 
for a single administration rather than daily injections. New evidence that G-CSF 
acts as a growth factor for neuroblastoma cancer stem cells (see section 2.1) 


 
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raises the concern that administration of this growth factor may be contributing to 
relapsed or refractory disease by stimulating the neuroblastoma cancer stem 
cells specifically.  This concern warrants re-evaluation of the strategy of using 
colony stimulating factors for primary prophylaxis in neuroblastoma. 
Granulocyte-macrophage colony stimulating factor (GM-CSF) is an 
alternative colony stimulating factor that acts on multiple cell lineages, including 
monocytes and neutrophils through binding its own surface receptor. It does not 
bind to the CD114 receptor found on neuroblastoma cancer stem cells, nor do 
neuroblastoma cells appear to have GM-CSF receptors. There have been few 
published trials of direct comparison of G-CSF with GM-CSF in children, 
however, these suggest little difference in overall efficacy, with GM-CSF 
demonstrating slightly longer time (1-2 days) to recover ANC compared with G-
CSF, but no difference in incidence of antibiotic administration for febrile 
neutropenia or length of hospitalization [24]. These data suggest GM-CSF may 
be a reasonable alternative to maintain dose intensity for patients who manifest 
significant infectious complications or delays between chemotherapy cycles. 
4.4 Infections in neuroblastoma patients during induction therapy 
 
A review of 76 patients treated for high risk neuroblastoma at Texas 
Children’s Hospital over the last ten years demonstrated that 58% of patients had 
one or more infections by the end of 5 cycles of induction chemotherapy (Table 
1). Each cycle, approximately 19% of patients had an infection (Table 2). These 
patients were treated with 5 cycles of induction chemotherapy of similar intensity 
to the proposed regimen for this study. Patients were treated with prophylactic G-


 
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CSF products (either filgrastim or peg-filgrastim) depending on the institutional 
standard of care at the time of treatment. Serious bacterial infections were 
defined as bacteremia with positive blood culture, signs/symptoms of sepsis with 
negative blood culture, pneumonia evident on chest radiograph with clinical 
symptoms, grade III urinary tract infection, grade III cellulitis and neutropenic 
enterocolitis. Review of Children’s Oncology Group data from patients treated 
using the same regimen proposed in this study revealed a similar average rate of 
infections of 15% per cycle for all cycles (ANBL 02P1 Study Committee Progress 
Report, Section III. Toxicities).  These data demonstrated the highest rate of 
infections after cycles 5 and 6, with an infection rate of 20% for these cycles.   
# of Serious infections 
# of patients (n=76) (%) 
0 
32 (42%) 
1 
25 (33%) 
≥2 
19 (25%) 
Table 1. Analysis of rates of serious bacterial infections for HR neuroblastoma 
patients at TCH. Charts from patients undergoing HR neuroblastoma induction 
chemotherapy treated at Texas Children’s Hospital from 2006-2015 were analyzed 
for serious bacterial infections. Number of infections per patient over 5 cycles is 
reported. 
 
Cycle 
Number with Serious bacterial 
Infection 
% With 
infection 
1 
14/76 
18.4% 
2 
13/75 
17.3% 
3 
13/73 
17.8% 
4 
17/71 
23.9% 
5 
11/70 
15.7% 
 
Table 2. Analysis of rates of serious bacterial infections for HR neuroblastoma 
patients at TCH. Charts from patients undergoing HR neuroblastoma induction 
chemotherapy treated at Texas Children’s Hospital from 2006-2015 were analyzed 


 
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for serious bacterial infections. Number of infections per cycle of chemotherapy is 
reported. 
 
 
4.5 Caregiver Burden 
 
The intensive treatment plan described above for high-risk neuroblastoma 
incurs a significant but poorly defined burden on the family. Having a child 
with cancer is associated with high financial costs [25] physical and 
psychological health of all members of the family and upheaval of normal 
family activities [26].  The frequency and duration of trips to the hospital and 
attending to medical needs of the child at home are two large contributors to 
family burden.  Measuring how treatment affects patients and their families 
allows the family experience to be included in the overall assessment of the 
care.  For example, a companion assessment of the leukemia clinical trials, 
P9904 and P9905, measured the family burden associated with inpatient 
versus outpatient methotrexate delivery. The pre-study assumption was that 
outpatient chemotherapy would be preferred, however they found that care 
was more burdensome and patient wellbeing was lower in the outpatient 
group [27].  This study examined care at one point in time.  It is unclear how 
the time and effort changes over time. 
 
The Care of My Child with Cancer (CMCC) instrument is a 28-item scale that 
measures the time and effort required to complete various tasks within the 
past week.  The estimated time to complete the survey is 10 minutes.   It is 
interpreted via physical and emotional subscales.  Initial validation 


 
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demonstrated it has an internal consistency coefficient of 0.93 and a test-
retest estimate of 0.9 with 3 to 7 days between administrations [28].  A 
second psychometric evaluation of the instrument was performed with 513 
caregivers that supported its internal reliability [29]. This instrument is 
available in English and Spanish versions.  This instrument was also used on 
ACCL01P3, the companion study to P9904 and P9905 described above.  
Completing this instrument in association with high-risk neuroblastoma 
induction therapy will allow description of the burden for this treatment. 
5 
ELIGIBILITY CRITERIA AND SUBJECT RECRUITMENT 
5.1 Inclusion Criteria: 
A. Age >12 months and <18 years old at diagnosis 
B. Newly diagnosed neuroblastoma or ganglioneuroblastoma as verified by 
histology and/or demonstration of tumor cells in bone marrow with elevated 
urinary catecholamine metabolites 
C. Must meet criteria for High Risk disease 
 
1. Patients with INSS stage 4 disease are eligible with the following 
o MYCN amplification (greater than four-fold increase in MYCN 
signals as compared to reference signals), regardless of age or 
additional biologic features 
o Age >18 months (>547 days) regardless of biologic features 
o Age 12-18 months (365-547 days) with any of the following 
unfavorable biologic features (unfavorable pathology and/or DNA 


 
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index =1) or any biologic feature that is 
indeterminate/unsatisfactory/unknown 
2. Patients with INSS stage 3 disease are eligible with the following 
o MYCN amplification, regardless of age or additional biologic 
features 
o Age >18 months (>547 days) with unfavorable pathology, 
regardless of MYCN status 
3. Patients with INSS stage 2a/2b with MYCN amplification regardless of 
age or additional biologic features 
4. Patients ≥365 days initially diagnosed with INSS stage 1 or 2 who 
progressed to a stage 4 without interval chemotherapy 
D. Patients may have had no prior systemic therapy except 
 Localized emergency radiation to sites of life threatening or functioning 
disease 
 No more than 1 cycle of chemotherapy according to low or intermediate 
risk regimens prior to determination of MYCN amplification and histology, 
as long as the patient DID NOT receive G-CSF as part of that therapy. 
E. Patients must have adequate hematopoietic function defined as 
 Absolute neutrophil count (ANC) ≥ 750/μL, 
 Platelet count ≥ 75,000/μL 
 The above criteria do not have to be met if the patient has bone marrow 
involvement of tumor. 
F. Patients must have adequate liver function defined as 


 
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 Direct bilirubin ≤ 1.5 mg/dL or total bilirubin ≤ 1.5 mg/dL 
 AST and ALT ≤ 10 x upper limit of normal for age. 
G. Patients must have adequate renal function as defined as: 
 Creatinine clearance (CrCl) or radioisotope GFR ≥70 mL/min/1.73 m2 OR 
 A serum creatinine based on age/gender as follows: 
Age 
Maximum Serum Creatinine (mg/dL) 
 
Male 
Female 
1 month to < 6 months
0.4 
0.4 
6 months to < 1 year
0.5 
0.5 
1 to < 2 years 
0.6 
0.6 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the Schwartz 
formula for estimating GFR (Schwartz et al. J. Peds, 106:522, 1985) utilizing 
child length and stature data published by the CDC. 
H.  Patients must have adequate cardiac function as defined as: 
 Shortening fraction of ≥ 27% by echocardiogram, or 
 Ejection fraction of ≥ 50% by radionuclide angiogram 
5.2 Exclusion Criteria 
A. Patients who do not meet inclusion criteria 
B. Patients who are pregnant or lactating.  
C. Patients who have received G-CSF since the time of diagnosis of the current 
disease 


 
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5.3 Subject Recruitment 
Subjects will be recruited from new patients with neuroblastoma presenting to 
Texas Children’s Cancer Center and Rady Children’s Hospital San Diego for 
treatment. 
5.4 Informed Consent 
Consent to participate in a research study will be obtained from the parent(s) or 
legal guardians prior to treatment.  Assent will be obtained from the child, when 
age appropriate according to guidelines of Baylor College of Medicine and Texas 
Children’s Hospital. 
 
5.5 Patient registration and study enrollment 
Patients may be enrolled on the study once all eligibility requirements for the 
study have been met. Eligibility checklist items will entered and uploaded into the 
electronic database eligibility section.  The local investigator will review the 
eligibility checklist and electronically confirm accuracy.  The coordinating center 
PI will then review the items and electronically confirm accuracy, at which point 
the subject will be considered registered and enrolled on study.   
 
6 
TREATMENT PLAN 
This treatment plan describes induction chemotherapy only, including 6 cycles of 
chemotherapy, tumor resection, and stem cell collection.  To ensure that safety 
data generated is directly comparable, the staging, disease evaluations and drug 


 
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administration will be followed according to our current practice and as close as 
possible to current national best practice. After two cycles of chemotherapy, 
disease reevaluation will take place including primary tumor imaging and bone 
marrow evaluation.  According to our institutional standard of care, peripheral 
blood stem cells will be harvested for high dose chemotherapy/autologous stem 
cell rescue (HST/SCR) after cycle 3 of induction chemotherapy.  The stem cell 
transplant itself, however, will take place after protocol therapy is completed. 
Surgical resection of the primary tumor will follow the fifth cycle of chemotherapy 
provided the tumor is deemed surgically resectable at that time. Consolidation 
therapy, including HDT/SCR and radiation therapy, and maintenance therapy will 
be conducted off-study according to the institutional standard. 
6.1 Induction Chemotherapy 
Induction chemotherapy will consist of six cycles of chemotherapy administered 
approximately 21 days apart. The first two cycles will be cyclophosphamide and 
topotecan.  Cycles 3 and 5 will consist of cisplatin and etoposide, and cycles 4 
and 6 will be cyclophosphamide, vincristine and doxorubicin. Disease re-
evaluation will occur after cycle 2, and again after cycle 6. This chemotherapy 
regimen is consistent with the current national best practice according to the 
Children’s Oncology Group. 
6.1.1 Criteria to receive chemotherapy 
Chemotherapy cycles (except cycle 1) may begin when the ANC is ≥750/μL and 
platelets ≥75,000/μL after post chemotherapy nadir.  There are no hematologic 
criteria to begin cycle 1. 


 
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Patients who received one cycle of chemotherapy per low or intermediate risk 
neuroblastoma therapy prior to determination of MYCN amplification and 
histology will receive all 6 cycles of induction chemotherapy on this protocol. 
6.2 Induction therapy administration 
 For patients >12 kg, chemotherapy doses will be calculated by body 
surface area (BSA). 
 For patients ≤12 kg, chemotherapy doses for all drugs EXCEPT topotecan 
will be dose per kg rather than per BSA. 
 Topotecan dosing will be based on BSA regardless of age or weight 
6.2.1 Induction therapy cycle 1 and 2 
 Cyclophosphamide 400 mg/m2/dose (or if ≤12 kg, 13.3 mg/kg) IV over 30-
60 minutes, once daily for 5 doses on days 1-5. 
 Topotecan 1.2 mg/m2/dose IV over 30 minutes, once daily for 5 doses on 
days 1-5. 
6.2.2 Induction therapy cycle 3 and 5 
 Cisplatin 50 mg/m2/dose (or if or if ≤12 kg, 1.66 mg/kg/dose) IV over 60 
minutes, once daily on days 1-4.  Suggest achieving urine specific gravity 
≤ 1.010 prior to start of cisplatin. 
 Etoposide 200 mg/m2/dose (or if ≤12 kg, 6.67 mg/kg/dose) IV over at least 
90 minutes, once daily for 3 doses on days 1-3. 
6.2.3 Induction therapy cycle 4 and 6 
 Cyclophosphamide 2100 mg/m2/dose (or if or if ≤12 kg, 70 mg/kg/dose) IV 
over 6 hours, once daily for 2 doses on days 1-2. 


 
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 MESNA 420 mg/m2/dose (or if or if ≤12 kg, 14 mg/kg/dose) IV immediately 
prior to each cyclophosphamide dose and again at 3, 6, 9 and 12 hours 
after the start of each cyclophosphamide infusion on days 1-2 
 Doxorubicin 25 mg/m2/dose (or if or if ≤12 kg, 0.83 mg/kg/dose) IV over 15 
minutes once daily for 3 doses. 
 Dexrazoxane 250 mg/m2/dose (or if ≤12 kg, 8.3 mg/kg/dose) once daily x3 
doses 
 Vincristine 
o Patients <12 months of age: 0.017 mg/kg/dose once daily IV for 3 
doses on days 1-3 
o Patients ≥ 12 months and ≤ 12 kg: 0.022 mg/kg/dose once daily IV 
for 3 doses on days 1-3 
o Patients ≥ 12 months and ≥ 12 kg: 0.67 mg/m2 once daily IV for 3 
doses on days 1-3 
6.3 Stem Cell Collection 
 
Patients will have peripheral blood stem cells harvested after the third cycle of 
chemotherapy, provided they are clinically stable enough to do so. G-CSF will be 
administered according to institutional standard procedures prior to stem cell 
collection. If adequate stem cell number is not able to be collected after cycle 3, 
re-collection will be attempted at a later time during induction chemotherapy.  


 
23
6.4 Local Control- Surgery 
6.4.1 Diagnostic Surgery 
In all patients, the goal of the first surgical procedure is to obtain enough tumor 
tissue for a histologic diagnosis and well as MYCN determination, cytogenetics 
and other biologic studies.  The surgeon should attempt to obtain at least 1cm3 of 
viable tumor tissue, if feasible, without putting the patient at undo risk.  Complete 
excision should only be undertaken if doing so is unlikely to delay the start of 
chemotherapy or result in great morbidity.   
6.4.2 Delayed Resection 
Surgical resection of soft tissue disease should be planned for after induction 
cycle 5 (or later, if medically necessary).  The goal of delayed resection is gross 
total resection of residual tumor in the primary site and any tumor in areas of 
regional dissemination (usually lymph nodes).  All attempts should be made to 
preserve organs.   
6.4.3 Prophylactic Growth factor prior to surgical resection 
To prevent potential delays between chemotherapy administration and surgical 
resection, prophylactic rGM-CSF will be administered following the 
chemotherapy cycle immediately prior to surgical resection until ANC >750/μL. 
CBC will be checked twice weekly while receiving rGM-CSF.  
6.5 Supportive Care 
6.5.1 Myeloid Growth factor 
No prophylactic G-CSF (filgrastim, peg-filgrastim) will be administered during this 
therapy with the exception of mobilization and harvesting of peripheral blood 
stem cells.  Prophylactic GM-CSF (sargramostim) will be administered prior to 


 
24
surgical resection and for patients who meet criteria for prophylactic GM-CSF 
administration for prior myelosuppression or prior infections (see sections 6.5.1 
and 6.5.3). 
If a subject is inadvertently given G-CSF (filgrastim or peg-filgrastim) rather than 
GM-CSF (sargramostim) for a cycle in which growth factor is indicated, this will 
be considered a protocol violation. These subjects will remain on protocol 
therapy.  
If a subject is inadvertently given one or two doses of G-CSF (filgrastim) during a 
cycle where no growth factor was indicated, this will be considered a protocol 
deviation, and the cycle will still be considered evaluable. If the subject is given 
more than two doses of filgrastim in a single cycle or is given a dose of peg-
filgrastim, that cycle will be considered inevaluable. If the subject is given more 
than two doses of filgrastim in two or more cycles or a dose of peg-filgrastim in 
two or more cycles, the subject will be removed from protocol therapy. 
6.5.2 Hematopoietic Support 
Patients should receive platelet and red cell transfusion as per institutional 
guidelines and optimal patient care. 
Complete blood count (CBC) should be checked twice weekly for patients with 
Grade 4 thrombocytopenia (<25,000/μL) and Grade 4 neutropenia (<500/μL). 
6.5.3 Nausea and vomiting 
Patients should receive anti-emetics as per institutional guidelines and optimal 
patient care. 


 
25
6.6 Dose modifications for toxicity during induction chemotherapy 
Toxicities will be graded by CTCAE version 4 criteria. Neurologic toxicity will be 
graded using Balis Criteria.  
6.6.1 Myelosuppression 
Chemotherapy may begin when ANC ≥ 750/μL and platelet count is ≥ 75,000/μL 
(except to start cycle 1 if patient has bone marrow involvement). Delay the next 
cycle until both criteria are met. 
Cycles should be approximately 21 days apart. Attempt to start all cycles on day 
22 following the start of previous cycle of chemotherapy. Following any cycle, if 
the ANC <750/ μL and/or platelet count is <75,000/ μL, delay next cycle until 
recovery occurs or meets criteria to continue based on bone marrow tumor 
involvement. If patient recovery to ANC ≥ 750/μL and platelet count is ≥ 
75,000/μL by day 29, proceed with next cycle at full dose. 
Delay beyond day 22 due to Platelets <75,000/μL 
 Recheck CBC in 1 week (day 29) 
Delay beyond day 29 due to Platelets <75,000/μL 
 If recovery occurs between day 30-43, reduce the doses of all drugs 
except vincristine by 25% 
 If recovery occurs after day 43 of any cycle, reduce all doses of drugs by 
50%, except for vincristine 
Delay beyond day 22 due to ANC <750/μL 
 If ANC ≥250/μL at day 22, continue to check CBC twice a week 
until ANC ≥750/μL, then begin chemotherapy at full dose. If ANC 


 
26
remains <750/μL at day 29, see below for Delays beyond day 29 
due to ANC<750/μL. 
 If ANC <250/μL at day 22, begin GM-CSF daily 250 mcg/m2 IV or 
SQ daily and check CBC twice weekly until ANC ≥750/μL, then 
begin chemotherapy at full dose. 
Delay beyond day 29 due to ANC <750/μL 
 If ANC <750/μL at day 29, begin GM-CSF 250 mcg/m2 IV or SQ daily and 
check CBC twice weekly until ANC ≥750/ μL.  For all future cycles of the 
chemotherapy that caused delay >29 days use prophylactic GM-CSF 250 
mcg/m2 IV or SQ daily. For example, if delay occurred after 
Topotecan/Cyclophosphamide, the next cycle of 
Topotecan/cyclophosphamide should include prophylactic GM-CSF 
 If recovery (ANC < 750/ μL by day 29) occurs more than once AND the 
second delay occurs while the patient is receiving growth factors, reduce 
all subsequent chemotherapy by 25% (except vincristine). 
6.6.2 Dosing of GM-CSF 
 250 mcg/m2 IV or SQ daily until ANC >750 x1 
6.6.3 Infections 
Patients who experience the following infectious complications will be treated 
with prophylactic GM-CSF (250 mcg/m2 IV or SQ daily until ANC ≥750/ μL x1) for 
ALL subsequent cycles of induction chemotherapy 
 Any grade IV bacterial infection 


 
27
 Any identified bacterial or presumed bacterial infection requiring IV 
antibiotics including 
o Bacteremia with positive blood culture 
o Signs/symptoms of sepsis with negative blood culture 
o Pneumonia evident on chest radiograph with clinical symptoms 
consistent with pneumonia 
o Grade III urinary tract infection 
o Grade III cellulitis 
o Neutropenic enterocolitis 
 
Hematuria  
For Cycles 1 and 2: If microscopic (> 2 abnormal urinalyses during a cycle of 
therapy with < Grade 2 hematuria) or gross hematuria occurs after Induction 
Cycle 1 cyclophosphamide, give MESNA with Induction Cycle 2 
cyclophosphamide as follows: MESNA 80 mg/m2 (or 2.67 mg/kg if < 12 kg) with 
cyclophosphamide infusion, then MESNA 80 mg/m2 (or 2.67 mg/kg if < 12 kg) IV 
over 15 minutes at Hours 4 and 8 from start of cyclophosphamide infusion. If 
hematuria resolves prior to start of cycle 4 cyclophosphamide, administer 
cyclophosphamide and mesna in cycles 4 and 6 without modification. 
 
For Cycles 4 and 6: If microscopic (> 2 abnormal urinalyses during a cycle of 
therapy with < Grade 2 hematuria) or gross hematuria occurs after Induction 
Cycle 4 cyclophosphamide, give mesna as a 24 hour continuous infusion with 
Induction Cycle 6 cyclophosphamide as follows: MESNA 2100 mg/m2(or 70 


 
28
mg/kg if < 12 kg) in required fluid over 24 hours starting with the start of the 
cyclophosphamide dose each day. 
 
If Grade 3 or 4 hematuria occurs following a cycle of cyclophosphamide, do not 
give another cycle of cyclophosphamide, topotecan (CT) or cyclophosphamide, 
doxorubicin and vincristine (CDV) until hematuria resolves to Grade 2 or less. If 
patient is due to begin next cycle of cyclophosphamide containing chemotherapy 
prior to resolution of hematuria to  Grade 2, substitute cisplatin and etoposide 
cycle. The intent of Induction is to give a total of 2 cycles each of CT, 
cisplatin/etoposide and CDV, therefore if substitution of cisplatin/ etoposide is 
made for CDV cycle or a CT cycle, make-up this missed cyclophosphamide-
containing cycle later in therapy. If gross hematuria from cyclophosphamide 
recurs, delete cyclophosphamide from subsequent cycles. 


 
29
6.6.4 Renal Toxicity 
6.6.4.1 Cisplatin 
No dose reductions in cisplatin will be made for a decrease in the 
baseline GFR or creatinine clearance as long as the value remains > 60 
mL/min/1.73 m2. If the serum creatinine increases > 50% during a cycle 
of cisplatin-containing chemotherapy, omit the remainder of the cisplatin 
from that cycle.  Repeat GFR prior to next scheduled cisplatin.  If GFR or 
creatinine clearance is < 60 mL/min/1.73 m2 prior to cisplatin/etoposide 
cycle substitute CDV cycle. The intent of Induction is to give a total of 2 
cycles of CT, 2 cycles of cisplatin/etoposide, and 2 cycles of CDV, 
therefore if substitution of CDV cycle is made for cisplatin/etoposide 
cycle, give the cisplatin/etoposide cycle later in therapy. Omit further 
cycles of cisplatin therapy if GFR or creatinine clearance remains < 60 
mL/min/1.73m2. 
Cyclophosphamide, Doxorubicin, Vincristine, Topotecan and Etoposide 
No dose reductions in cyclophosphamide, doxorubicin, vincristine, topotecan or 
etoposide are necessary for decrease in creatinine clearance. 


 
30
6.6.5 Cardiac Toxicity 
6.6.5.1 For Symptomatic Congestive Heart Failure (CHF) 
If at any time, the patient develops Grade 3 congestive heart failure or 
dysrhythmia or any Grade 4 cardiac toxicity not related to underlying 
infection or metabolic abnormality, omit doxorubicin from all subsequent 
cycles. If cardiac toxicity is resolved to < Grade 2 congestive heart failure 
or dysrhythmia, decrease the dose of cyclophosphamide to 50% for the 
next cycle containing cyclophosphamide. If this dose of 
cyclophosphamide is tolerated without > Grade 2 congestive heart failure 
or dysrhythmia, then decrease the dose of cyclophosphamide to 50% for 
the next cycle containing cyclophosphamide. If this dose of 
cyclophosphamide is tolerated without > Grade 2 congestive heart failure 
or dysrhythmia, then administer full dose of cyclophosphamide in 
subsequent cycles of chemotherapy. 
6.5.5.2 For Dysrhythmia 
If the patient develops Grade 2 cardiac dysrhythmia as defined in the Common 
Toxicity Criteria, repeat in one week. If Grade 2 toxicity resolves to Grade 0 or 1 
toxicity, patient may continue on therapy without chemotherapy dose alterations. 
If Grade 2 toxicity occurs prior to Cycle 4, substitute cisplatin/etoposide for CDV 
cycle until dysrhythmia resolves. Make a notation of chemotherapy substitution 
on data form. The intent of Induction is to give a total of 2 cycles of CDV and 2 
cycles of cisplatin/etoposide, therefore if cisplatin/etoposide cycle substituted for 


 
31
CDV, give CDV cycle later in therapy. If dysrhythmia symptoms occur prior to 
Cycle 6, proceed with cyclophosphamide, vincristine but omit doxorubicin. 
6.5.5.3 Hypertension 
Hypertension due to neuroblastoma will not be considered reason for removal 
from protocol therapy or alteration in chemotherapy doses. 
6.5.6 Hepatotoxicity  
If direct bilirubin is > 3 mg/dL prior to Cycle 4 chemotherapy, substitute 
cisplatin/etoposide for CDV cycle. If direct bilirubin is > 3 mg/dL prior to Cycle 6 
chemotherapy, omit doxorubicin and vincristine. If direct bilirubin is > 1.5 but < 3 
(Grade 3 toxicity) prior to Cycle 4 or 6 chemotherapy, reduce doxorubicin and 
vincristine dose by 50%. 
6.5.7 Gastrointestinal Toxicity 
6.5.7.1 Mucositis 
If patient develops Grade 3 or 4 mucositis that resolves to < Grade 2 by Day 22-
29 of next cycle, no dose adjustments will be made in chemotherapy and no 
prophylactic growth factor will be administered. If patient develops Grade 3 or 4 
mucositis that is NOT attributable to infectious etiology AND recovery to < Grade 
2 occurs between Day 30-43 for any cycle of Induction, administer GM-CSF for 
all subsequent cycles of chemotherapy.   For the second occurrence of Grade 3 
or 4 mucositis that resolves to < grade 2 by day 30-43 reduce the dose of 
doxorubicin or etoposide in the next 2 cycles of chemotherapy by 25%. If 
subsequent chemotherapy tolerated without recurrence of Grade 3 or 4 GI 


 
32
toxicity then resume full doses of chemotherapy agents in all subsequent cycles 
of induction. 
If patient develops Grade 3 or 4 mucositis that is NOT attributable to infectious 
etiology AND recovery to < Grade 2 occurs after Day 43 of any cycle, administer 
GM-CSF for all subsequent cycles of chemotherapy.   For the second occurrence 
of Grade 3 or 4 mucositis that resolves to < grade 2 after day 43 of any cycle 
reduce dose of doxorubicin or etoposide in the next 2 cycles of chemotherapy by 
50%. If subsequent chemotherapy tolerated without recurrence of Grade 3 or 4 
GI toxicity then escalate dose by 25% in subsequent cycles of induction. 
If patient develops mucositis that requires intubation for airway management or if 
patient develops grade 4 neutropenic enterocolitis or other grade 4 
gastrointestinal toxicity hold subsequent chemotherapy until toxicity resolved to < 
Grade 2. If the toxicity resolves to < Grade 2 by Day 43, proceed with next 2 
cycles of chemotherapy but administer prophylactic GM-CSF and reduce dose of 
doxorubicin or etoposide by 25%. If recovery to < Grade 2 occurs after Day 43 of 
any cycle, administer prophylactic GM-CSF and reduce dose of doxorubicin or 
etoposide in the next 2 cycles of chemotherapy by 50%. If subsequent 
chemotherapy tolerated without recurrence of Grade 3 or 4 GI toxicity then 
escalate dose by 25% in subsequent cycles of induction. 
6.5.7.2 Diarrhea 
If patient develops severe diarrhea (Grade 3 or 4) attributable to chemotherapy 
and not underlying infection (i.e. C. difficile), that resolves by Day 22-29 of cycle, 


 
33
no dose adjustments will be made in chemotherapy. If recovery to < Grade 2 
occurs between Day 30-43 for any cycle of Induction, reduce the dose of 
doxorubicin or etoposide in next cycle of chemotherapy by 25%. If subsequent 
chemotherapy tolerated without recurrence of Grade 3 or 4 GI toxicity then 
resume full doses of chemotherapy agents in all subsequent cycles of induction. 
If recovery to < Grade 2 occurs after Day 43 of any cycle, reduce dose of 
doxorubicin or etoposide in the next cycle of chemotherapy by 50%. If 
subsequent chemotherapy tolerated without recurrence of Grade 3 or 4 GI 
toxicity then escalate dose by 25% in subsequent cycles of induction. 
6.5.8 Ototoxicity  
For an inner ear/hearing toxicity  Grade 3, decrease cisplatin dose by 50% for 
subsequent cycles. If loss extends below 2000 Hz, delete further 
cisplatin/etoposide cycles. If cisplatin is deleted, then complete total of 2 cycles of 
CDV, then proceed to consolidation therapy.  
6.5.9 Neurologic Toxicity  
If severe peripheral neuropathy (vocal cord paralysis, inability to walk or perform 
usual motor functions) or ileus develops from vincristine, vincristine therapy 
should be stopped or withheld until the ileus resolves or the peripheral 
neuropathy improves. Restart vincristine at 50% dose and escalate by 25% if 
tolerated with next course. If neuropathy recurs on escalating dose, return to 
previously tolerated dose once neuropathy improved. 


 
34
6.5.10 Allergic Reactions 
4.5.10.1 Etoposide 
Etoposide allergic reactions may be managed with diphenhydramine 1mg/kg IV 
(maximum single dose 50 mg), ranitidine 1 mg/kg IV (maximum single dose 50 
mg) and hydrocortisone 2 mg/kg IV (maximum single dose 100 mg) and by 
slowing the rate of the infusion. For those reactions which are unable to be 
controlled with medication and the slowing of the rate of etoposide infusion, 
etoposide phosphate may be substituted in the same dose and at the same rate. 
Pre-medication for etoposide phosphate is recommended. 
6.5.10.2 Cisplatin and Carboplatin 
Platinum allergic reactions may be managed with diphenhydramine 1mg/kg IV 
(maximum dose 50mg), ranitidine 1mg/kg IV (maximum single dose 50 mg) and 
Hydrocortisone 2 mg/kg IV (maximum single dose 100 mg). 
 
6.7 Drug Shortages 
In the event of a drug shortage of a medication that is not a G-CSF or GM-CSF 
product, the provider may use best clinical judgment regarding omission of the 
agent or substitution with a different agent. The medical and research records of 
study patients should reflect that the patient was informed of any delays and/or 
modifications in protocol therapy related to the shortage of the agent and the 
associated risks. 


 
35
7 
STUDIES TO BE OBTAINED WHILE ON PROTOCOL THERAPY 
7.1 Required Observations 
Observation 
Pre-
Treatment 
Before 
each 
cycle 
Weekly 
After 
cycle 2 
After 
cycle 6 
CBC 
x 
x 
x∧ 
 
 
Chem 10, AST, 
ALT, Bili 
x 
x 
 
 
 
GFR/Serum Cr 
x 
 
 
x* 
 
Audiogram/ABER 
(Suggested only) 
x 
 
 
 
x 
EKG 
 
 
 
 
x 
ECHO 
x 
 
 
 
x 
Tumor imaging 
with CT or MRI  
x 
 
 
x 
x 
MIBG (preferred) 
or bone scan or 
PET scan  
X$ 
 
 
x 
x 
Bilateral BM 
Aspirate and 
biopsy 
x 
 
 
x# 
x# 
Urine HVA and 
VMA 
x 
 
 
x# 
x# 
Urine Pregnancy 
Test % 
x 
 
 
 
 
Care of My Child 
with Cancer 
instrument 
 
Before 
cycle 2 
and 5& 
 
 
 
∧Twice weekly while on growth factors 
# if positive/elevated at diagnosis 
* if abnormal at diagnosis 
% if female of childbearing potential 
& Optional study 
$ Within 2 weeks of enrollment if unable to obtain prior to diagnosis 
8 
EVALUATION CRITERIA 
8.1 International Response Criteria [30] 
o Complete response (CR): No evidence of primary tumor; no evidence of 
metastases (chest, abdomen, liver, bone, bone marrow, nodes, etc.), and 
HVA/VMA normal. MIBG scan must be negative to qualify for CR. 


 
36
o Very good partial response (VGPR): Greater than 90% reduction in 
primary tumor; no metastatic tumor (as above except bone); no new bone 
lesions, all pre-existing lesions improved, HVA/VMA normal 
o Partial Response (PR): 50-90% reduction of primary tumor; 50% or 
greater reduction in measurable sites of metastases; 0-1 bone marrow 
samples with tumor; number of positive bone sites decreased by 50% 
o Mixed Response (MR): Greater than 50% reduction of any measurable 
lesion (primary or metastases) with, <50% reduction in any other site; no 
new lesions; <25% increase in any existing lesion (exclude bone marrow 
evaluation). 
o No response (NR): No new lesions; <50% reduction by <25% increase in 
any existing lesion (exclude bone marrow evaluation). 
o Progressive disease (PD): Any new lesion or increase of a measurable 
lesion by 25%; previous negative marrow positive for tumor. Any new site 
of disease documented by MIBG scan qualifies patient as having 
progressive disease. 
 
9 
DRUG INFORMATION 
9.1 Sargramostim (Granulocyte macrophage colony stimulating factor, 
rhu GM-CSF, rGM-CSF, GM-CSF) 
Source and pharmacology: 
Sargramostim (recombinant human GM-CSF) is a glycoprotein produced in yeast 
(S. cerevisiae) by recombinant DNA technology. rGM-CSF is a hematopoietic 
growth factor which supports survival, clonal expansion, and differentiation of 


 
37
hematopoietic progenitor cells. rGM-CSF induces partially committed progenitor 
cells to divide and differentiate in the granulocyte-macrophage pathways. rGM-
CSF stimulates the production of monocytes, granulocytes, erythrocytes, and 
sometimes, megakaryocytes in the bone marrow. It also induces mature 
neutrophil and monocytes to increase phagocytosis, superoxide generation, 
ADCC, tumoricidal killing and cytokine production (IL-1 and tumor necrosis 
factor). Recombinant human GM-CSF is a glycoprotein of 127 amino acids 
characterized by three primary molecular masses of 15500, 16800, and 19500 
daltons. The amino acid sequence differs from the natural sequence by a 
substitution of leucine at position 23 and the CHO moiety may be different from 
the native protein. After subcutaneous administration of sargramostim, peak 
levels were obtained in 1-4 hours and were detectable at therapeutic levels for 
12-16 hours post injection. The elimination t½ ranges from 1.5-2.7 hours after 
SubQ or IV administration. 
Toxicity 
 
Common 
21-100 children 
out of every 100 
Occasional 
5-20 children out of 
100 
Rare  
<5 children out of 
every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Headache, 
malaise, fatigue, 
rash, pruritus, 
bone pain, 
myalgia, 
arthralgia, fever, 
chills 
Abdominal Pain, 
weakness, 
anorexia, nausea, 
local injection 
reactions 
Anaphylaxis, “first 
dose reaction” 
(hypoxia, 
dyspnea, 
hypotension, 
fever, 
tachycardia, 
diaphoresis, 
flushing, back 
pain), vomiting, 
diarrhea, 
phlebitis, SVT, 


 
38
pericardial 
effusion 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
 
Weight gain 
In high doses: 
capillary leak 
syndrome, 
pneumonitis, 
peripheral 
edema, elevation 
of creatinine, 
bilirubin and 
hepatic enzymes 
in patients with 
pre-existing renal 
or hepatic 
dysfunction 
Delayed: 
Any time later 
during therapy 
 
Thrombocytopenia 
 
Unknown 
frequency and 
Timing 
Fetal and teratogenic toxicities: It is not known whether 
sargramostim can cause fetal harm or affect reproduction 
capacity when administered in pregnant women. It is 
unknown whether the drug is excreted in breast milk 
 
Formulation and Stability: 
Sargramostim is available as a lyophilized sterile, white, preservative free powder 
with 250 mcg (1.4 million International Units) per vial. The sargramostim 
reconstituted lympholized vial contains 40 mg/mL mannitol, USP, as excipients. 
Do not freeze or shake. 
Reconstitute lyophilized powder for injection with 1 mL SWFI or 1 mL 
Bacteriostatic Water for Injection. Use SWFI without benzyl alcohol for 
neonates, infants, and children < 2 years of age or patients with 
hypersensitivity to benzyl alcohol. During reconstitution, direct the diluent at 
the side of the vial and gently swirl the contents to avoid foaming during 
dissolution. Avoid excessive or vigorous agitation; do not shake. Reconstituted 


 
39
solutions prepared with Bacteriostatic Water for Injection (0.9% benzyl alcohol) or 
the liquid preserved solution may be stored for up to 20 days following the first 
entry into the vial at 2°-8°C (36°-46°F). Discard reconstituted solution after 20 
days have elapsed. Reconstituted solutions prepared with SWFI (without 
preservative) should be administered as soon as possible and within 6 hours 
following reconstitution. 
 
Use sargramostim for subcutaneous injection without further dilution. Perform 
dilution for IV infusion in NS. If the final concentration is < 10 mcg/mL, add 
albumin (human) at a final concentration of 0.1% to the saline prior to addition of 
sargramostim to prevent adsorption to the components of the drug delivery 
system. For a final concentration of 0.1% albumin (human), add 1 mg albumin 
(human) per 1 mL NS. For example, for a final volume of 50 mL NS, add 50 mg 
(or 1 mL) of 5% albumin [human]. Intravenous dilutions are stable for up to 48 
hours at room temperature or refrigerated but should be used within 6 hours due 
to microbiological concerns. Do not use an in-line membrane filter for IV infusion. 
Supplier: Commercially available. See package insert for more detailed 
information.  
 
10 OFF THERAPY AND OFF STUDY CRITERIA 
10.1 Off Therapy Criteria 
A. Tumor related 
o Progressive or recurrent disease at any time such that provider feels it 


 
40
is in patient’s best interest to proceed to alternative chemotherapeutic 
agents not included in this protocol 
B.  Treatment related 
o Unacceptable toxicity necessitating change in treatment plan. 
o Greater than two doses of G-CSF (filgrastim) in two or more cycles or 
a dose of peg-filgrastim in two or more cycles administered in a cycle 
when prophylactic growth factor was not indicated 
10.2 Off Study Criteria 
o Death 
o Patient/parent request to discontinue participation on the protocol 
o Patient becomes pregnant 
 
11 SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS 
Subjects on study will have scheduled clinic visits and laboratory evaluations 
throughout the treatment period. During these visits, they will be closely monitored 
for clinical or laboratory evidence of toxicity associated with the administered 
chemotherapy. Adverse events related to the omission of hematopoietic growth 
factors will be collected.  Each grade ≥3 adverse event will be collected for the 
following targeted adverse events: febrile neutropenia, bacterial infection, 
bacteremia, pneumonia, urinary tract infection, cellulitis, and neutropenic 
enterocolitis.  Hematologic toxicities including neutropenia, anemia, and 
thrombocytopenia will be collected. Adverse events will be scored utilizing criteria 
listed in the Common Terminology Criteria for Adverse Events (CTCAE) version 


 
41
4.0. For multiple occurrences of a toxicity in a single cycle, a separate grade will 
be listed for each occurrence.  Further assessment, testing, and interventions for 
any adverse events will be at the discretion of the subject's primary clinician, unless 
specified in section 6.6 Dose Modifications for Toxicities: 6.6.1 Myelosuppression 
and 6.6.3 Infection. 
An Unanticipated Problem Involving Risk to Subjects or Others (UPIRSO) is 
defined as incident, experience or outcome that is unexpected (in terms of the 
nature, severity or frequency) given (a) the description of the likely harms in the 
protocol, the consent form or the other materials submitted to the IRB and (b) the 
characteristics of the subject population; related to a subject's participation in the 
research; and suggests that the research places subjects or others at greater risk 
of harm - physical, psychological, economic or social harms - than was previously 
known or recognized. Study subjects should be advised to report any UPIRSOs 
they experience during the course of their participation in this study from time of 
consent through the end of the study. 
All unanticipated problems involving risks to subjects or others (UPIRSOs) should 
be identified and reported locally per institutional standards. All UPIRSOs should 
be entered into the electronic database within 24 hours of study personnel 
becoming aware of the event.  
 
The Principal Investigator will provide a Continuing Review Report to the Dan L. 
Duncan Data Review Committee (DRC) annually. The BCM IRB will be provided 
with the DRC’s determination at every renewal. In addition, all unexpected events 


 
42
that increase the subject’s risk of harm considered by the Principal Investigator to 
be possibly, likely, or definitely related to not receiving G-CSF or administration of 
GM-CSF or participation in this study will be reported to the IRB office per their 
policies. Expected adverse events will not be reported.  
All safety data collected on study participants will be reviewed on a continuous 
basis for any evidence of a higher-than-expected incidence of adverse events. 
Since the study will not be blinded, it will be feasible to determine on an ongoing 
basis whether there is a higher incidence of adverse events or toxicities than 
expected. Any evidence for such a discrepancy will be brought to the attention of 
the DRC and then the IRB and the cumulative data will be reviewed to determine 
the suitability of continuing the study. 
11.1 Follow-up 
Adverse events (as defined in section 11) for all patients will be documented and 
reported to the Principal Investigator until the subject’s ANC has recovered to 
greater than 1000 (units) (post-nadir) after cycle 6 chemotherapy or until the 
subject is removed from protocol therapy for progressive disease. 
12 DATA COLLECTION, STUDY MONITORING, AND CONFIDENTIALITY 
The study data will be captured through an electronic database. The Clinical Trials 
Management System (CTMS) is a secure web-based system. The CTMS is HIPAA 
compliant and 21 CFR Part 11 compliant to protect the integrity of trial data. The 
CTMS establishes individual user accounts to control access to site-specific 
patient data. All registered users will be assigned a unique user account to log in 
to the system. Access is restricted to the roles granted to the user by the 


 
43
coordinating center. External sites will only be able to view data for patients 
enrolled at their center. Study personnel will periodically review study accrual, 
study procedures, and integrity and completeness of the data collected. 
This study will undergo quality analysis per the Texas Children’s Hospital 
monitoring policy.  All patient eligibility will be reviewed by the study PI prior to 
enrollment. 
 
13 FINANCIAL CONSIDERATIONS 
The therapeutic components of this study will be paid for by the patient's usual 
methods of reimbursement. GM-CSF will be paid for by the patient’s usual 
methods of reimbursement. The cost of treatment of infections will also be 
covered by the patient’s usual methods of reimbursement whether or not the 
patient received prophylactic growth factor prior to developing the infection. 
 
14 POTENTIAL RISKS AND BENE FITS 
The potential risks of this therapy are substantial. The risk associated with the 
research question, not giving prophylactic G-CSF, is the potential that the patient 
will have increased risk of serious infections and/or delays in chemotherapy.  
There is a small possibility that substantial delays in therapy may lead to an 
increase in relapse or refractory disease.  These will be mitigated with the 
addition of GM-CSF to reduce excessive delays when indicated. 
Untreated, high-risk neuroblastoma is invariably fatal.  The chemotherapy 
outlined in this protocol has been associated with improved survival in previous 


 
44
trials; therefore there is a potential benefit to receiving the chemotherapy 
associated with this study. While G-CSF is considered a standard part of 
treatment for high-risk neuroblastoma, there is little data to support its need.  It is 
possible the patient may benefit by not receiving a drug they do not need.  If G-
CSF increases neuroblastoma tumor cell growth, patients may benefit from not 
receiving this agent.    
14.1 Risks of Chemotherapy Agents: 
Possible Side Effects of Cisplatin   (Table Version Date: April 20, 2015) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, more than 20 and up to 100 may have: 
 Nausea, vomiting,  
 Infection, especially when white blood cell count is low 
 Anemia which may cause tiredness, or may require blood transfusions 
 Bruising, bleeding 
 Kidney damage which may cause swelling, may require dialysis 
 Hearing loss including ringing in ears 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cisplatin, from 4 to 20 may have: 
 Hair loss 
 Change in taste 
 Diarrhea  
 Allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat 
 Confusion 
 Difficulty with balance 
 Numbness and tingling of the arms and legs 
 Blurred vision or changes in ability to see colors (especially blue or yellow) 
 
RARE, AND SERIOUS 
In 100 people receiving Cisplatin, 3 or fewer may have: 
 Cancer of bone marrow caused by chemotherapy later in life 
 Seizure 
 
Possible Side Effects of Cyclophosphamide  
(Table Version Date: May 28, 2013) 


 
45
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Cyclophosphamide, more than 20 and up to 100 
may have: 
 Hair loss 
 Nausea, vomiting, loss of appetite 
 Sores in mouth 
 Infection, especially when white blood cell count is low 
 Absence of menstrual period which may decrease the ability to have 
children 
 Blood in urine 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Cyclophosphamide, from 4 to 20 may have: 
 Damage to the bone marrow (irreversible) which may cause infection, 
bleeding, may require transfusions 
 Loss or absence of sperm which may lead to an inability to father children 
 Stuffy nose 
 Fluid around the heart 
 
RARE, AND SERIOUS 
In 100 people receiving Cyclophosphamide, 3 or fewer may have: 
 Severe skin rash with blisters and peeling which can involve mouth and 
other parts of the body 
 Damage to the heart or heart failure which may cause shortness of breath, 
swelling of ankles, cough or tiredness 
 A new cancer including cancer of bone marrow (leukemia) caused by 
chemotherapy 
 Swelling of the body including the brain which may cause dizziness, 
confusion 
 Scarring of the lungs 
Possible Side Effects of Dexrazoxane (Table Version Date: October 24, 
2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Dexrazoxane, more than 20 and up to 100 may 
have: 
 Infection, especially when white blood cell count is low 
 Nausea 
 Fever 
 Bruising, bleeding 
 


 
46
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Dexrazoxane, from 4 to 20 may have: 
 Allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat 
 Anemia which may cause tiredness, or may require transfusion 
 Pain at the site of injection 
 Vomiting 
 
RARE, AND SERIOUS 
In 100 people receiving Dexrazoxane, 3 or fewer may have: 
 Cancer of bone marrow caused by chemotherapy 
Possible Side Effects of Doxorubicin   (Table Version Date: October 24, 
2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Doxorubicin, more than 20 and up to 100 may have:
 Hair loss 
 Vomiting 
 Red colored urine, saliva, or sweat  
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Doxorubicin, from 4 to 20 may have: 
 Heart failure or heart attack which may cause shortness of breath, swelling 
of ankles, cough or tiredness which may occur years after the dose 
 Swelling of the body which may cause shortness of breath 
 Swelling and redness at the site of the medication injection or area of 
previous radiation 
 Belly pain 
 Sores in the mouth, throat or stomach 
 Nausea, diarrhea 
 Hepatitis which may cause yellow eyes and skin 
 Allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat 
 Cancer of the bone marrow (leukemia) caused by chemotherapy 
 Damage to organs which may cause infection, bleeding, may require 
transfusions 
 Darkening of the nail beds or skin or hands and feet 
 Loss of nails 
 
RARE, AND SERIOUS 
In 100 people receiving Doxorubicin, 3 or fewer may have: 
 Infection, especially when white blood cell count is low 
 Bruising, bleeding 
 Severe blood infection 


 
47
 Possible Side Effects of Etoposide  (Table Version Date: May 28, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Etoposide, more than 20 and up to 100 may have: 
 Hair loss 
 Chills 
 Sores in mouth which may cause difficulty swallowing 
 Diarrhea, loss of appetite, nausea, vomiting 
 Infection, especially when white blood cell count is low 
 Anemia which may require transfusion 
 Bruising, bleeding 
 Tiredness 
 Fever 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Etoposide, from 4 to 20 may have: 
 Heart failure or heart attack which may cause chest pain, shortness of 
breath, swelling of ankles, and tiredness 
 Severe skin rash with blisters and peeling which can involve inside of 
mouth and other parts of the body 
 Liver damage which may cause yellowing of eyes and skin, swelling 
 
RARE, AND SERIOUS 
In 100 people receiving Etoposide, 3 or fewer may have: 
 Cancer of bone marrow caused by chemotherapy 
 Allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat 
Possible Side Effects of Filgrastim  (Table Version Date: October 24, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Filgrastim, more than 20 and up to 100 may have: 
 Nausea, vomiting 
 Pain in bone 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Filgrastim, from 4 to 20 may have: 
 Anemia which may cause tiredness, or may require transfusion 
 Damage to the lungs which may cause shortness of breath 
 Internal bleeding which may cause coughing up blood 
 Swelling or tenderness of vessels 
 
RARE, AND SERIOUS 
In 100 people receiving Filgrastim, 3 or fewer may have: 
 Rupture of the spleen leading to bleeding in the belly 


 
48
Possible Side Effects of Mesna (Table Version Date: May 28, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Mesna, more than 20 and up to 100 may have: 
 Nausea, vomiting 
 Tiredness, headache 
 Pain in arms, legs 
 Unpleasant taste 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Mesna, from 4 to 20 may have: 
 Low blood pressure which may cause feeling faint 
 
RARE, AND SERIOUS 
In 100 people receiving Mesna, 3 or fewer may have: 
 None 
Possible Side Effects of Sargramostim (Table Version Date: October 24, 
2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Sargramostim, more than 20 and up to 100 may 
have: 
 Diarrhea, vomiting 
 Internal bleeding which may cause black tarry stool, or blood in vomit 
 Pain 
 Chills, fever, tiredness 
 Infection 
 Weight loss 
 Itching, rash 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Sargramostim, from 4 to 20 may have: 
 Abnormal heartbeat 
 Bleeding of the eye which may cause blurred vision with a chance of 
blindness 
 Difficulty swallowing 
 Swelling of arms, legs 
 Bleeding in the brain which may cause headache, confusion 
 Worry 
 Kidney damage which may cause swelling, may require dialysis 
 Fluid in the organs which may cause low blood pressure, shortness of 
breath, swelling of ankles 
 


 
49
RARE, AND SERIOUS 
In 100 people receiving Sargramostim, 3 or fewer may have: 
 None 
Possible Side Effects of Topotecan (Table Version Date: April 22, 2014) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Topotecan, more than 20 and up to 100 may have: 
 Anemia which may require a blood transfusion 
 Constipation, diarrhea, nausea, vomiting 
 Fever 
 Pain 
 Bruising, bleeding 
 Infection, especially when white blood cell count is low 
 Tiredness 
 Shortness of breath 
 Hair loss 
 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Topotecan, from 4 to 20 may have: 
 Sores in mouth which may cause difficulty swallowing 
 Headache 
 Cough 
 Scarring of the lungs 
 Rash 
 
RARE, AND SERIOUS 
In 100 people receiving Topotecan, 3 or fewer may have: 
 Allergic reaction which may cause rash, low blood pressure, wheezing, 
shortness of breath, swelling of the face or throat 
Possible Side Effects of Vincristine (Table Version Date: May 28, 2013) 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving Vincristine, more than 20 and up to 100 may have: 
 Constipation 
 Hair loss 
 Pain or redness at the site of injection 
 Numbness and tingling of fingers or toes 
 Headache, jaw pain and/or muscle pain 
 Weakness and difficulty walking 
 Swelling of lower legs 
 


 
50
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving Vincristine, from 4 to 20 may have: 
 Anemia which may cause tiredness, or may require transfusion 
 Drooping eyelids 
 Hoarseness 
 
RARE, AND SERIOUS 
In 100 people receiving Vincristine, 3 or fewer may have: 
 Seizure 
14.2 Risks of stem cell collection 
The risks of peripheral blood stem cell collection are the risks of apheresis, which 
are minimal. The specific risks to the individual patient will be explained in detail 
prior to the procedure by the apheresis team and consent for this procedure will 
be obtained separately at that time. 
14.3 Risks of surgery 
The risks of surgical resection are numerous including infection, hemorrhage and 
death.  The specific risks to the individual subject are dependent on the extent 
and location of disease at time of resection. These risks will be explained in detail 
and consent for surgery will be obtained by the surgeon prior to surgery. 
 
15 STATISTICAL CONSIDERATIONS 
15.1 Statistical design 
 
Sample size was calculated based on an estimation of infection rate for patients 
receiving prophylactic G-CSF of 58% (see section 4.4). This study will use 
Ahern’s single stage design. A total of 13 subjects will be enrolled into this study. 
We will reject the null hypothesis if the proportion of patients who do NOT 


 
51
develop an infection is ≤22% in favor of the alternative hypothesis that the 
proportion is ≥42% if at least 5 of 13 subjects complete six cycles of therapy 
without an infection. If the true proportion is 22%, then the probability of 
incorrectly rejecting the null hypothesis is 15% (type 1 error). If the true 
proportion is 42%, then the probability of failing to reject the null hypothesis is 
25% (type II error).   
 
15.2 Patient accrual and expected duration of trial 
Texas Children’s Hospital sees approximately 10-12 new high risk 
neuroblastoma patients per year. We plan to enroll 13 patients total. We 
anticipate this protocol will reach accrual goals in 2 to 2.5 years. The trial 
duration will be approximately 3 years.  
An additional 13 caregivers will be enrolled to participate on the assessment of 
caregiver burden survey. 
The expected duration of the trial for individual subjects is approximately 21 
weeks.   
 
15.3 Statistical analysis methods 
15.3.1 Aim 1 
The primary endpoint of this study is the incidence of the following infections in 
chemotherapy cycles NOT followed by hematopoietic growth factors: 
 Any grade IV bacterial infection 
 Any identified bacterial or presumed bacterial infection requiring IV 
antibiotics including 


 
52
o Bacteremia with positive blood culture 
o Signs/symptoms of sepsis with negative blood culture 
o Pneumonia evident on chest radiograph with clinical symptoms 
consistent with pneumonia 
o Grade III urinary tract infection 
o Grade III cellulitis 
o Neutropenic enterocolitis 
This study will conclude that the proportion of patients who develop one of the 
above infections following cycles of chemotherapy when they did not receive 
hematopoietic growth factor is non-inferior to that of the standard regimen if 14 or 
fewer out of 21 total evaluable patients develop an infection. Otherwise, we will 
conclude that the new treatment regimen is not significantly non-inferior. The 
proportion of patients who develop an infection will be estimated with 95% 
confidence intervals using the methods of Koyama and Chen [31].  
15.3.2 Secondary Aims: 
The remainder of the aims will be descriptive in nature.  We will use descriptive 
statistics to evaluate time between chemotherapy cycles, time to neutrophil 
recovery, antibiotic days, hospital days due to fever and/or infection and number 
of platelet transfusions.  We will also describe response rates for patients 
enrolled in this study. 
 
 Aim 2.1 To determine the incidence and duration of delay in 
chemotherapy administration due to prolonged neutrophil recovery in 


 
53
patients undergoing induction chemotherapy for high-risk neuroblastoma 
without prophylactic G-CSF 
We will capture start dates of each chemotherapy cycle reasons for delay 
cycles are >21 days apart.  Assessment will be performed via descriptive 
analysis, calculating the proportion of each cycle delayed by cause of 
delay. 
  
 Aim 2.2 To determine the number of antibiotic days and hospital days due 
to fever and/or infection for in patients undergoing induction chemotherapy 
for high-risk neuroblastoma without prophylactic G-CSF 
We will capture start and stop dates for antimicrobial agents (except 
agents for prevention of infection such as PJP prophylaxis agents and 
prophylactic anti-fungal agents).  Admission and discharge dates for 
admissions for fever or documented or possible  infection will be captured.  
Assessment of this aim will be performed via descriptive analytics 
summarizing the number of days of antibiotics and admitted to hospital for 
infection and compared by cycles with and without growth factors.   
  
 Aim 2.3 To determine the number of platelet transfusions in in patients 
undergoing induction chemotherapy for high-risk neuroblastoma without 
prophylactic G-CSF 


 
54
We will capture each platelet transfusion.  Assessment of this aim will be 
performed via descriptive analytics summarizing the number platelet 
transfusions and compared by cycles with and without growth factors.   
 
 Aim 2.4 To describe the response rate following induction chemotherapy 
without prophylactic G-CSF for patients with high-risk neuroblastoma 
Assessment of this aim will be performed via a descriptive analysis, 
calculating the number and proportion of patients in each response 
category and the proportion who achieve a CR, VGPR or PR after 
induction. 
 
 Aim 2.5 To describe caregiver burden in patients  undergoing induction 
chemotherapy for high risk neuroblastoma  
Assessment of this aim will be performed via a descriptive analysis, 
calculating the scores of the CMCC survey after cycle 1 and cycle 4.  
Summary statistics at each time point will be estimated.  The individual 
scores and the change in scores for each patient will be compared to 
demographic factors and toxicities to identify potential predictors of 
increased caregiver burden for future study.   
 
15.4 Gender and minority analysis 
Given the low accrual of 13 patients, it is unlikely that a meaningful analysis of 
minorities is feasible. We shall report outcome and toxicity in a qualitative 


 
55
manner by gender and race. No formal statistical comparisons will be applied to 
these subgroups. 
 
16  ASSESSMENT OF FAMILY BURDEN 
Participation in this aspect of this trial is voluntary. 
Primary caregivers (one from each family) will complete the Care of My Child 
with Cancer instrument twice during induction: between day 21 and 29 of cycle 1 
(before starting cycle 2) and between day 21 and 29 of cycle 4 (before starting 
cycle 5). The instrument will be completed in paper version, and kept with the 
research chart.  It is not necessary that the same primary caregiver complete 
both surveys. Responses will be reviewed in real time by the research staff.  
 
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