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\begin{document}

\title{Tolerability of ifosfamide-containing regimen in patients with high-risk
renal and INI-1-deficient tumors}



\author[1]{Chris I. Wong}%
\author[2]{Daniel Benedetti}%
\author[3]{Pei-Chi Kao}%
\author[4]{Clement Ma}%
\author[3]{Karen Marcus}%
\author[3]{Elizabeth Mullen}%
\affil[1]{University Hospitals Rainbow Babies \& Children's Hospital}%
\affil[2]{Vanderbilt Department of Pediatrics}%
\affil[3]{Dana-Farber/Boston Children's Cancer and Blood Disorders Center}%
\affil[4]{Centre for Addiction and Mental Health}%


\vspace{-1em}



  
  \date{May 26, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Outcomes for children with high-risk renal (HRR)
and INI-1-deficient (INI-) tumors are unacceptably poor. Concerns about
excessive toxicity -- as many are infants and/or undergo nephrectomy --
have resulted in decreased chemotherapy dosing and omission of the
nephrotoxic drug ifosfamide in collaborative group studies. As cause of
death for children with these cancers remains overwhelmingly more from
progressive disease rather than treatment toxicity, we examined the
tolerability of an intensive ifosfamide-containing-regimen.
\textbf{Procedure:} Retrospective review of children with HRR/INI-
tumors treated at a single institution with vincristine, doxorubicin,
cyclophosphamide alternating with ifosfamide, carboplatin, etoposide
(VDC-ICE) from 2006-2016. The primary outcome was regimen tolerability
including kidney injury and grade 3-5 non-hematologic toxicities.
\textbf{Results:} Fourteen patients with a median age of 1.7 years
(range 0.1-10.5) treated with VDC-ICE were identified. Diagnosis
included malignant rhabdoid tumor (n=9) {[}primary renal (n=2){]};
diffuse anaplastic Wilms tumor (n=3); clear cell sarcoma of the kidney
(n=1); and anaplastic chordoma (n=1). All children with primary renal
tumors (43\%) underwent complete (n=5) or partial nephrectomy (n=1)
before chemotherapy. Nine (64\%) completed all intended cycles of
chemotherapy; n=5 (36\%) did not due to disease progression. Unplanned
hospitalizations occurred in 13 (93\%) patients, most commonly for
febrile neutropenia. No patient experienced severe organ toxicity,
diminished renal function, treatment discontinuation due to toxicities,
or treatment-related death. \textbf{Conclusions:} In children with
HRR/INI- tumors, VDC-ICE chemotherapy was well-tolerated without
excessive toxicities, even amongst young patients with solitary kidneys.
Concerns about toxicity should not preclude an intensive
ifosfamide-containing regimen from use in future trials in this
population.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Outcomes for children with advanced stage high-risk renal (HRR) tumors,
such as malignant rhabdoid tumors (MRT), diffuse anaplastic Wilms tumors
(DAWT), and clear cell sarcoma of the kidney (CCSK), are markedly worse
than for favorable histology Wilms Tumor.\textsuperscript{1-5} Large
collaborative group trials, such as Children's Oncology Group's (COG)
AREN0321, have improved outcomes for some children with HRR tumors using
increasingly intensive, multi-agent chemotherapy regimens. Yet for MRT
and other INI-1 deficient (INI-) tumors, which can also occur outside
the kidney, outcomes remain dismal. Chemotherapy for HRR/INI- tumors
typically combines common agents, such as vincristine, doxorubicin,
cyclophosphamide, carboplatin, and etoposide. Prospective studies,
including the National Wilms Tumor Study Group studies and COG AREN0321,
have omitted ifosfamide from upfront use due to concerns about
nephrotoxicity in these patients, many of whom require nephrectomy.
Toxicity concerns have also limited therapy intensification strategies
that have been successful in other aggressive pediatric malignancies.

Despite prospective trial avoidance of upfront ifosfamide, a few case
studies have reported patients with MRT successfully treated using
alternating cycles of vincristine, doxorubicin, and cyclophosphamide
(VDC) and ifosfamide, carboplatin, and etoposide (ICE). However,
ICE-containing therapies can be nephrotoxic and potentially difficult to
tolerate in very young children, particularly those who receive a
nephrectomy. These tolerability concerns have limited the use of ICE and
other ifosfamide-containing regimens in patients with HRR/INI- tumors,
despite its use for relapsed renal tumors and other aggressive pediatric
solid tumors.\textsuperscript{9-11} Further analysis is needed to
evaluate the effectiveness and tolerability of VDC-ICE as front-line
therapy in these children.

Beginning in 2006, our institution implemented a standard treatment
plan, alternating cycles of VDC and ICE (hereafter referred to as
VDC-ICE), for patients presenting with HRR/INI- tumors and offered it to
patients who were not eligible for or refused an open clinical trial at
the time of presentation. We now report upon the clinical course,
complications, and toxicities experienced by our patients treated with
this regimen.

\textbf{METHODS}

We retrospectively reviewed the medical records of pediatric patients
treated at the Dana-Farber/Boston Children's (DF/BC) Cancer and Blood
Disorders Center with the VDC-ICE treatment plan and diagnosed from
January 2006 to December 2016. Patients were identified through a search
of the Pediatric Patient Informatics Platform and electronic
chemotherapy order entry reports detailing treatment plans. These
reports were reviewed for their accuracy. Patients were excluded if --
despite receiving a recommendation for this treatment plan or beginning
this treatment plan at DF/BC -- they completed the bulk of the treatment
at another institution or had shared cared with another institution, as
all details on toxicity were not available. General characteristics of
these patients were captured as available but were not included in the
analysis. Data collected on the population of interest included patient
demographics, treatment plan, and clinical course, as well as
complications, toxicities, and outcomes. This study was approved by the
Dana-Farber Cancer Institute Institutional Review Board.

\textbf{VDC-ICE treatment plan}

The core treatment plan was adapted from published dosing and
administration schedules. The plan consists of eight alternating cycles
of VDC and ICE given intravenously. Cycles of VDC consist of
cyclophosphamide 1800-2100 (higher dose for MRT)
mg/m\textsuperscript{2}given on day 1, doxorubicin 37.5
mg/m\textsuperscript{2} given days 1 and 2 (or a single dose on day 1),
and vincristine 1.5 mg/m\textsuperscript{2} given days 1, 8, and 15 (or
a single dose on day 1). Cycles of ICE consist of carboplatin at a
target AUC of 6 mg/ml-min given on day 1, with ifosfamide 2000
mg/m\textsuperscript{2} and etoposide 100 mg/m\textsuperscript{2} given
days 2, 3, and 4. Mesna was administered for bladder protection with all
doses of cyclophosphamide or ifosfamide, per institutional standards.
Growth factor with filgrastim or pegfilgrastim, and cardioprotection
with dexrazoxane (dosed at 10 times the doxorubicin dose as 375
mg/m\textsuperscript{2}), were administered per institutional standards
to all patients. Cycles were three weeks in duration, with an allowable
interruption of up to two weeks for surgical resection of the primary or
residual tumor. Radiation therapy was recommended concurrently with
chemotherapy. Modifications in chemotherapy doses or changes to the
order of chemotherapy cycles (e.g., giving consecutive ICE cycles to
avoid anthracyclines concurrently with radiation) were at the discretion
of the patient's oncologist. Supportive care often included aggressive
and extended anti-emetic regimens and extended supplemental intravenous
fluid replacement.

\textbf{Tolerability, complications, and toxicity}

The primary aim of this study was to describe the complications and
toxicity associated with this treatment plan. Data were abstracted from
the record, described categorically, and graded using the common
terminology criteria for adverse events version 5 (CTCAE v5.0).
Information abstracted included: unplanned hospitalizations and
admissions to the intensive care unit (ICU), unplanned ambulatory clinic
or emergency department (ED) visits (not for scheduled chemotherapy,
routine examinations, or restaging); significant infections, such as
central line-associated bloodstream infection, and treatment delays. A
treatment delay was defined as an interval of greater than four weeks
between chemotherapy cycles (one week longer than expected) or greater
than five weeks if surgery was performed (two weeks longer than expected
without surgery). Organ toxicity (except for hematopoietic and transient
minor elevation of liver function tests), admissions for fever and
neutropenia, uncontrolled nausea, and vomiting were recorded and graded.
Long-term toxicities (organ toxicities grades 3 and 4) and impact on
growth were noted in follow-up until the last contact at the time of
record abstraction.

\textbf{Outcomes}

Data examined included whether remission, relapse, or death from disease
progression occurred and the patients' vital status at last contact.

\textbf{Data collection and statistical analyses}

Two trained pediatric oncology physicians (DJB and CIW) abstracted data
from the patients' medical records using a standardized data collection
form in REDCap, an electronic data management platform. The form was
first pilot-tested by the two clinicians and modified to ensure the data
of interest was collected. To ensure consistency, the two clinicians met
before abstracting data and throughout data collection to reach
consensus on definitions. Each clinician also independently reviewed two
records that had been abstracted by the other and no discrepancies were
found. Descriptive statistics were used to summarize patient
demographics, clinical characteristics, toxicities, and outcomes,
including frequencies and proportions for categorical variables and
medians and ranges for continuous variables. Statistical analyses were
performed using SAS version 9.4 (SAS Institute, Cary, NC).

\textbf{RESULTS}

\textbf{Patient characteristics}

Fourteen patients received VDC-ICE therapy as described in Table 1. The
median age at diagnosis was 1.7 years (range=0.1-10.5), and 50\% were
male (n=7) and 79\% Caucasian (n=11). The most common diagnosis was
non-kidney MRT (n=7), followed by DAWT (n=3), MRT of the kidney (n=2),
CCSK (n=1), and anaplastic chordoma (n=1). Six patients had metastatic
disease (stage IV), with the kidney (n=6) or soft tissue (n=6) being the
most common primary disease sites. Five patients received previous
treatment, and 6 patients underwent complete or partial nephrectomy
prior to chemotherapy.

\textbf{Therapy details}

Chemotherapy and local control therapies are described in Table 2. Nine
patients (64\%) completed the intended 8 cycles of VDC-ICE chemotherapy.
In the five remaining patients (36\%), the planned treatment regimen was
discontinued for disease progression. Three patients (21\%) received
additional chemotherapy concurrently with VDC-ICE. This additional
chemotherapy for all three patients consisted of cycles of vincristine
and irinotecan (VI) intermixed with VDC-ICE, as data emerged that the
addition of VI improved outcome for patients with DAWT.

For the 9 patients who completed treatment, the median cumulative dose
received was 6000 mg/m\textsuperscript{2} of cyclophosphamide
(range=4800-8400), 24 g/m\textsuperscript{2} of ifosfamide
(range=21-24), and 270 mg/m\textsuperscript{2} of doxorubicin
(range=135-450). All patients received dexrazoxane as cardio-protection
with doxorubicin, and all received growth factor after each chemotherapy
cycle.

Local control therapy consisted of surgery and/or radiation. Nine (64\%)
patients received radiation to the primary site of disease, and 3 (21\%)
received additional radiation to metastatic sites. Most (n=7/9; 78\%)
patients received radiation therapy concurrent with chemotherapy. Ten
patients underwent some form of surgical resection, which was performed
upfront, prior to chemotherapy initiation, in 6 patients. Complete
surgical resection was achieved in 70\% (n=7/10) of all patients who
underwent resection and in 78\% (n=7/9) of patients who received
radiation therapy.

\textbf{Complications and toxicity}

Cycle-specific toxicities are described in Table 3. A total of 87 cycles
of VDC or ICE were received; 45 were VDC cycles, and 42 were ICE cycles.
Seven (16\%) VDC cycles were associated with chemotherapy delays
compared to 4 (10\%) ICE cycles. The most common reason for chemotherapy
delay was delayed count recovery. Febrile neutropenia was the most
common complication observed, seen in 20 (44\%) VDC cycles and 18 (43\%)
ICE cycles. Unplanned hospitalizations were seen in 22 (49\%) of VDC
cycles and 22 (52\%) of ICE cycles, most commonly due to febrile
neutropenia. Similarly, 28 (62\%) VDC cycles and 36 (86\%) of ICE cycles
were associated with an unplanned visit to the ED or clinic, for reasons
such as blood product transfusions, fever evaluation, and symptom
management.

VDC cycles were also associated with 1 (2\%) electrolyte disturbance and
1 (2\%) hemorrhagic cystitis, both grade 1. No VDC cycles led to acute
kidney injury or resulted in the need for home hydration.

ICE cycles were further complicated by 1 (2\%) grade 1 acute kidney
injury (with rapid recovery) and 2 (5\%) minor electrolyte disturbance.
Five (12\%) led to the use of pre-emptively arranged home hydration for
future subsequent cycles after experiencing significant delayed nausea
and vomiting post carboplatin in an initial cycle. No ICE cycles were
associated with hemorrhagic cystitis.

Overall, among 14 patients treated with VDC-ICE therapy, 13 (93\%) had
an unplanned admission to the hospital (Supplemental Table S1). All
patients had unplanned ED/clinic visits (Supplemental Table S1).
Thirteen patients (93\%) experienced at least one episode of Grade 3
febrile neutropenia, and 8 (57\%) patients experienced grade 3
anorexia/malnutrition (Table 4). Other Grade 3 criteria observed
included: nausea/vomiting/dehydration (n=7); diarrhea (n=1); hypotension
in the setting of hematemesis (n=1); peripheral neuropathy (n=1); and
bacteremia (n=1). No non-hematologic grade 4 or 5 toxicities were
observed. Other complications patients experienced included acute kidney
injury (n=1) and hepatotoxicity (n=2) (Table 3 and 4). For the patients
with hepatotoxicity, tumor burden likely was a contributory factor.
Hepatotoxicity occurred only in patients with underlying diagnosis of
MRT of the liver. Two (14\%) patients required escalation of care to the
ICU during therapy (Supplemental Table S1), both of which were found to
have progressive disease shortly after ICU admission. Another patient
was transferred from a different institution to the ICU due to
complications that began prior to their first cycle of VDC-ICE
chemotherapy, so this ICU admission was not attributed to the treatment
plan.

There was no documented ototoxicity or clinically significant
cardiotoxicity, defined as a decrease in ejection fraction of greater
than 15 percent. Seven patients (50\%) experienced chemotherapy
administration delays. Six (43\%) patients had delays during VDC cycles,
and 4 (29\%) experienced delays during ICE cycles (Table 3). Eight
patients (57\%) required chemotherapy dose modifications, with the most
commonly modified drug being vincristine (n=5), followed by doxorubicin
(n=3), carboplatin (n=3), ifosfamide (n=2), and etoposide (n=2)
(Supplemental Table S1). No treatment-related mortality was observed.

\textbf{Outcomes}

Of the 14 patients who received VDC-ICE chemotherapy, 8 (57\%) achieved
clinical remission (Supplemental Table S2). Eight patients (57\%)
experienced relapse or progressive disease, of which 50\% had disease at
a new site different than the original sites of disease. At the time of
data collection, 56\% (n=5) of patients with MRT were alive (including
both patients with MRT of the kidney), as well as all patients with DAWT
(n=3), CCSK (n=1), and anaplastic chordoma (n=1).

\textbf{DISCUSSION}

Across an 11-year period at our institution, fourteen patients (5 with
single kidney) were treated with an intensive ifosfamide-containing
VDC-ICE treatment plan. This regimen was well tolerated, with no patient
experiencing toxicities severe enough to prevent completion of planned
therapy, and no significant renal toxicity occurred in any patient.
Although only 9 out of 14 patients completed all 8 intended cycles of
chemotherapy, early termination of VDC-ICE chemotherapy was only due to
disease progression, not lack of tolerability. There were no toxic
deaths or severe organ toxicities. While examining outcomes was not our
primary objective, our results add to existing evidence of an
association of improved outcomes with the use of intensified treatment.

The COG clinical trial, AREN0321, found that chemotherapy regimens (UH-1
and UH-2) containing nearly all of the same agents as VDC-ICE, with the
notable omission of ifosfamide, improved relapse-free survival for
stages II-IV DAWT. The UH-1 and UH-2 regimens were accompanied by
significant treatment-related CTCAE grade 4 toxicities and mortality --
with four patients with DAWT (6\%) dying of toxicities -- prompting a
reduction in regimen intensity and eventual early termination of the
trial. As VDC-ICE is similar or even more intense than UH-1
(Supplemental Table S3), we examined the toxicities experienced by our
patients receiving VDC-ICE. Importantly, we did not observe any
non-hematologic grade 4 or 5 toxicities. As the most significant
complications of AREN0321 were related to cardiac and pulmonary
dysfunction, we hypothesize that the universal use of the
cardioprotectant dexrazoxane in our study, which was allowed but not
recommended on AREN0321, may have contributed to the lack of grade 4 and
5 toxicities. However, future studies are needed to confirm this
hypothesis. Additional supportive care, including administration of
prophylactic infectious measures may have helped decrease infectious
complications, but these were not administered in a standardized way.
Kidney function may have been protected by extended home hydration
implementation.

The potential nephrotoxicity of ifosfamide-containing regimens like
VDC-ICE is a major concern in patients with HRR tumors, especially those
with single kidneys. In our cohort, kidney injury was rare, with just a
single episode of temporary grade 1 acute kidney injury due to an
episode of dehydration associated with carboplatin-induced delayed
nausea and vomiting, which resolved in 24 hours. Six of our patients had
primary renal tumors, all of whom underwent bilateral partial or
unilateral nephrectomies prior to the majority of their chemotherapy.
All six completed the intended 8 cycles of VDC-ICE, making the lack of
severe toxicity or renal insufficiency noteworthy in light of the
inclusion of the potentially nephrotoxic ifosfamide in VDC-ICE as
compared to the AREN0321 regimens. Possible explanations include
improvements in antiemetic management with more widespread use of
aprepitant and the ability to provide home hydration via nasogastric
tube or intravenous fluids. We acknowledge that our institution's
catchment area has excellent home nursing resources, enabling us to
offer these options to our patients.

Despite meticulous supportive care, the VDC-ICE regimen is not without
toxicities. Not surprisingly, given the myelosuppression expected with
the agents and doses administered, all but one patient (who only
received 3 cycles of VDC-ICE due to disease progression) experienced at
least one CTCAE grade 3 toxicity, each having at least one
hospitalization for febrile neutropenia. Half of our patients had grade
3 nausea/vomiting/dehydration, and more than half had anorexia requiring
nutritional support through a nasogastric tube. Other significant
toxicities were rare and limited to one episode of uncomplicated
bacteremia, hepatotoxicity in patients with tumors of their livers, and
admissions to the ICU. While 14\% (2/14) of patients requiring ICU
admission seems substantial, none were thought to be related to VDC-ICE
chemotherapy.

Although all patients treated with this regimen required significant
supportive care (e.g., unplanned ED/clinic visits, transfusion, and
nutritional support), it appears that overall, the complications and
toxicities observed in our cohort were manageable. Even though treatment
delays of greater than a week were observed in 50\% of our patients,
these were mostly due to delayed count recovery. Furthermore, this is
not entirely unexpected given the intensity of this regimen and does not
justify considering this regimen as intolerable. Other regimens, such as
standard of care for Ewing sarcoma (interval compressed alternating
cycles of VDC and ifosfamide/etoposide), are also plagued by the need
for significant symptomatic and supportive care, treatment delays, and
admissions for febrile neutropenia. Yet, this regimen has been used for
years as the standard of care for this disease, lasts longer than
VDC-ICE (28 versus 24 weeks) and has higher cumulative doses of
doxorubicin (375 mg/m\textsuperscript{2}), cyclophosphamide (8400
mg/m\textsuperscript{2}), ifosfamide (63 g/m\textsuperscript{2}), and
etoposide (3500 mg/m\textsuperscript{2}).

Our findings are limited by the small number of patients and their
management at our single institution. It is possible that the lack of
toxic deaths we have seen is due to chance alone. For example, given
toxic deaths on AREN0321 were rare, if the toxic death rate of VDC-ICE
were comparable to UH-1 and UH-2 regimens, we would have expected to see
just 1 toxic death in our 14 patients. Even discounting toxic death
rates, it is notable that our patients experienced no grade 4
toxicities. Because these tumors are rare, the challenge of low patient
numbers is difficult to overcome even through multicenter trials.
Nevertheless, we represent a high-volume center, and this is the largest
cohort of patients with HRR/INI- tumors described with this chemotherapy
regimen. The other similarly-sized cohort of pediatric oncology patients
treated with VDC-ICE comprised patients with Ewing sarcoma who were much
older, lacked renal tumors, and thus would have been expected to
tolerate the regimen better than our cohort.\textsuperscript{9}

Additionally, because this represents a retrospective analysis,
controlling for differences in patient characteristics, treatment
regimen administration, or supportive care is difficult. Each patient's
treatment plan was developed by our center's disease-specific expert in
renal tumors and MRT, with some patients receiving customized dosing or
the addition of other chemotherapy agents based on individual
characteristics. Therefore, whether our experience is generalizable
remains an important question.

Our findings suggest that VDC-ICE chemotherapy can be safely used for
children with HRR and INI-deficient tumors, with comparable toxicity to
other widely accepted pediatric oncology regimens. Most notably, use of
ifosfamide was tolerated without nephrotoxicity in a population
generally thought of as being at unacceptably high-risk of renal
toxicity. Despite the known activity of ifosfamide in HRR/INI- tumors,
the use of post-nephrectomy ifosfamide has been reserved for the
relapsed setting. Yet for patients with these aggressive malignancies,
for whom death is overwhelmingly due to progressive and relapsed disease
rather than treatment toxicity, withholding effective agents is
difficult to justify. With our findings of excellent tolerance of
VDC-ICE combined with no meaningful chance of post-relapse survival for
patients with these tumors, inclusion of ifosfamide in upfront treatment
regimens is imperative. The use of this regimen has been adopted as our
standard of care for these rare malignancies and should be considered as
a reasonable option until future studies identify more promising
treatments. Furthermore, we believe this regimen warrants further
evaluation at a greater scale through a prospective, multicenter
clinical trial.

\textbf{CONFLICT OF INTEREST}

The authors report no conflicts of interest.

\textbf{ACKNOWLEDGMENTS}

We want to thank Catriona Wagner, who provided medical writing
assistance. Our work would not have been possible without her
assistance, and we are very grateful for her contributions.

\textbf{References}

1. Jain J, Sutton KS, Hong AL. Progress Update in Pediatric Renal
Tumors. \emph{Curr Oncol Rep} . 2021;23(3):33.
doi:10.1007/s11912-021-01016-y

2. Daw NC, Chi Y-Y, Kim Y, et al. Treatment of stage I anaplastic Wilms'
tumour: a report from the Children's Oncology Group AREN0321
study.\emph{Eur J Cancer} . 2019;118:58-66.
doi:10.1016/j.ejca.2019.05.033

3. Daw NC, Chi Y-Y, Kalapurakal JA, et al. Activity of Vincristine and
Irinotecan in Diffuse Anaplastic Wilms Tumor and Therapy Outcomes of
Stage II to IV Disease: Results of the Children's Oncology Group
AREN0321 Study. \emph{J Clin Oncol} . 2020;38(14):1558-1568.
doi:10.1200/jco.19.01265

4. Wagner L, Hill DA, Fuller C, et al. Treatment of Metastatic Rhabdoid
Tumor of the Kidney. \emph{J Pediatric Hematology Oncol} .
2002;24(5):385-388. doi:10.1097/00043426-200206000-00012

5. Yamamoto M, Suzuki N, Hatakeyama N, et al. Treatment of Stage IV
Malignant Rhabdoid Tumor of the Kidney (MRTK) With ICE and VDCy. \emph{J
Pediatric Hematology Oncol} . 2006;28(5):286-289.
doi:10.1097/01.mph.0000212901.84146.5a

6. Marina NM, Poquette CA, Cain AM, Jones D, Pratt CB, Meyer WH.
Comparative Renal Tubular Toxicity of Chemotherapy Regimens Including
Ifosfamide in Patients With Newly Diagnosed Sarcomas. \emph{J Pediatric
Hematology Oncol} . 2000;22(2):112-118.
doi:10.1097/00043426-200003000-00007

7. Santos MLC, Brito BB de, Silva FAF da, Botelho AC dos S, Melo FF de.
Nephrotoxicity in cancer treatment: An overview. \emph{World J Clin
Oncol} . 2020;11(4):190-204. doi:10.5306/wjco.v11.i4.190

8. Rossi R, G\selectlanguage{ngerman}ödde A, Kleinebrand A, et al. Unilateral nephrectomy and
cisplatin as risk factors of ifosfamide-induced nephrotoxicity: analysis
of 120 patients. \emph{J Clin Oncol} . 1994;12(1):159-165.
doi:10.1200/jco.1994.12.1.159

9. Milano GM, Cozza R, Ilari I, De Sio L, Boldrini R, Jenkner A, De
Ioris M, Inserra A, Dominici C, Donfrancesco A. High histologic and
overall response to dose intensification of ifosfamide, carboplatin, and
etoposide with cyclophosphamide, doxorubicin, and vincristine in
patients with high-risk Ewing sarcoma family tumors: the Bambino Gesù
Children's Hospital experience. \emph{Cancer} . 2006 Apr
15;106(8):1838-45. doi: 10.1002/cncr.21780. Erratum in: Cancer. 2006 Sep
15;107(6):1421. PMID: 16532434.

10. Abu-Ghosh AM, Krailo MD, Goldman SC, Slack RS, Davenport V, Morris
E, Laver JH, Reaman GH, Cairo MS. Ifosfamide, carboplatin and etoposide
in children with poor-risk relapsed Wilms' tumor: a Children's Cancer
Group report. \emph{Ann Oncol.} 2002 Mar;13(3):460-9. doi:
10.1093/annonc/mdf028.

11. Spreafico F, Bisogno G, Collini P, Jenkner A, Gandola L, D'Angelo P,
Casazza G, Piva L, Luksch R, Perotti D, Pession A, Fagioli F, Dallorso
S. Treatment of high-risk relapsed Wilms tumor with dose-intensive
chemotherapy, marrow-ablative chemotherapy, and autologous hematopoietic
stem cell support: experience by the Italian Association of Pediatric
Hematology and Oncology. \emph{Pediatr Blood Cancer.} 2008
Jul;51(1):23-8. doi: 10.1002/pbc.21524.

12. Ma C, Sridharan M, Al-Sayegh H, et al. Building a Harmonized
Datamart by Integrating Cross-Institutional Systems of Clinical,
Outcome, and Genomic Data: The Pediatric Patient Informatics Platform (
PPIP ). \emph{Jco Clin Cancer Informatics} . 2021;5(5):202-215.
doi:10.1200/cci.20.00083

13. Venkatramani R, Shoureshi P, Malvar J, Zhou S, Mascarenhas L. High
dose alkylator therapy for extracranial malignant rhabdoid tumors in
children. \emph{Pediatr Blood Cancer} . 2014;61(8):1357-1361.
doi:10.1002/pbc.25093

14. Sepe DM, Ginsberg JP, Balis FM. Dexrazoxane as a Cardioprotectant in
Children Receiving Anthracyclines. \emph{Oncol} . 2010;15(11):1220-1226.
doi:10.1634/theoncologist.2010-0162

15. Jones DP, Chesney RW. Renal toxicity of cancer chemotherapeutic
agents in children. \emph{Curr Opin Pediatr} . 1995;7(2):208-213.
doi:10.1097/00008480-199504000-00016

16. Abu-Ghosh AM, Krailo MD, Goldman SC, et al. Ifosfamide, carboplatin
and etoposide in children with poor-risk relapsed Wilms' tumor: a
Children's Cancer Group report. \emph{Ann Oncol} . 2002;13(3):460-469.
doi:10.1093/annonc/mdf028

17. Daw NC, Gregornik D, Rodman J, et al. Renal function after
ifosfamide, carboplatin and etoposide (ICE) chemotherapy, nephrectomy
and radiotherapy in children with wilms tumour. \emph{Eur J Cancer} .
2009;45(1):99-106. doi:10.1016/j.ejca.2008.09.017

18. Grier HE, Krailo MD, Tarbell NJ, et al. Addition of Ifosfamide and
Etoposide to Standard Chemotherapy for Ewing's Sarcoma and Primitive
Neuroectodermal Tumor of Bone. \emph{New Engl J Medicine} .
2003;348(8):694-701. doi:10.1056/nejmoa020890

19. Eaton BR, Claude L, Indelicato DJ, et al. Ewing
sarcoma.\emph{Pediatr Blood Cancer} . 2021;68(S2):e28355.
doi:10.1002/pbc.28355

20. 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. \emph{J Clin
Oncol} . 2012;30(33):4148-4154. doi:10.1200/jco.2011.41.5703

\par\null

\textbf{TABLE 1.} Patient characteristics\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
& Total patients (n=14)\tabularnewline
\midrule
\endhead
Age at diagnosis (years), median (range) & 1.7 (0.1-10.5)\tabularnewline
Gender (male), \emph{n} (\%) & 7 (50)\tabularnewline
Race, \emph{n} (\%) &\tabularnewline
White & 11 (79)\tabularnewline
Asian & 1 (7)\tabularnewline
Other & 2 (14)\tabularnewline
Ethnicity, \emph{n} (\%) &\tabularnewline
Not Hispanic or Latino & 14 (100)\tabularnewline
Hispanic or Latino & 0 (0)\tabularnewline
Diagnosis, \emph{n} (\%) &\tabularnewline
Malignant rhabdoid tumor, non-kidney & 7 (50)\tabularnewline
Diffuse anaplastic Wilms tumor & 3 (21)\tabularnewline
Malignant rhabdoid tumor of the kidney & 2 (14)\tabularnewline
Clear cell sarcoma of the kidney & 1 (7)\tabularnewline
Anaplastic chordoma & 1 (7)\tabularnewline
Stage, \emph{n} (\%) &\tabularnewline
I & 0 (0)\tabularnewline
II & 1 (7)\tabularnewline
III & 6 (43)\tabularnewline
IV & 6 (43)\tabularnewline
V & 1 (7)\tabularnewline
Primary site, \emph{n} (\%) &\tabularnewline
Kidney & 6 (43)\tabularnewline
Liver & 2 (14)\tabularnewline
Soft Tissue & 6 (43)\tabularnewline
Previous treatment, \emph{n} (\%) &\tabularnewline
Yes & 5 (36)\tabularnewline
No & 9 (64)\tabularnewline
Nephrectomy prior to chemotherapy, \emph{n} (\%) & 6 (43)\tabularnewline
Complete & 5 (36)\tabularnewline
Partial & 1(7)\tabularnewline
\bottomrule
\end{longtable}

\textbf{TABLE 2.} Therapy details\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Total patients (n=14)\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
Total patients (n=14)\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Number of VDC-ICE cycles completed/patient\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Number of VDC-ICE cycles completed/patient\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}8 cycles\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\textless{}8 cycles\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (36)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5 (36)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8 cycles\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
8 cycles\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
9 (64)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
9 (64)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Additional concurrent regimen administered\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Additional concurrent regimen administered\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (21)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
3 (21)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
11 (79)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
11 (79)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Planned chemotherapy dose per cycle, median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Planned chemotherapy dose per cycle, median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
cyclophosphamide (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
cyclophosphamide (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1500 (1200-2100)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1500 (1200-2100)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
doxorubicin (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
doxorubicin (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
45 (45-75)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
45 (45-75)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
ifosfamide (gm/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
ifosfamide (gm/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (6-6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (6-6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
vincristine (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
vincristine (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4.5 (2-4.5)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4.5 (2-4.5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
carboplatin (AUC target, mg/ml-min)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
carboplatin (AUC target, mg/ml-min)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (6-6)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (6-6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
etoposide (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
etoposide (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
300 (300-300)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
300 (300-300)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Received dexrazoxane\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Received dexrazoxane\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
14 (100)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
14 (100)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Received growth factor after every cycle\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Received growth factor after every cycle\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
14 (100)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
14 (100)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cumulative chemotherapy dose (for patients who completed treatment),
median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Cumulative chemotherapy dose (for patients who completed treatment),
median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
cyclophosphamide (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
cyclophosphamide (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6000 (4800-8400)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6000 (4800-8400)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
ifosfamide (g/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
ifosfamide (g/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
24 (21-24)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
24 (21-24)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
doxorubicin dose (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
doxorubicin dose (mg/m\textsuperscript{2})\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
270 (135-450)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
270 (135-450)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Received radiation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Received radiation\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (64)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (64)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Primary site, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Primary site, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (64)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9 (64)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Flank\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Flank\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (22)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (22)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Other\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Other\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (78)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7 (78)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Metastatic site, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Metastatic site, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (21)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3 (21)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Lung\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Lung\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (67)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
2 (67)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Bone\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Bone\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (33)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1 (33)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Timing of radiation, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Timing of radiation, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Pre-chemotherapy\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Pre-chemotherapy\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (11)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (11)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
During chemotherapy\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
During chemotherapy\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (78)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (78)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Post-chemotherapy\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Post-chemotherapy\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (11)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (11)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age at radiation (years), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age at radiation (years), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3.4 (1.6-11.2)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3.4 (1.6-11.2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Underwent surgical resection, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Underwent surgical resection, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10 (71)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10 (71)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Complete resection\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Complete resection\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (54)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
7 (54)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Gross resection\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Gross resection\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (15)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2 (15)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (8)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1 (8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Timing of surgical resection, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Timing of surgical resection, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Upfront\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Upfront\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (60)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
6 (60)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
After neoadjuvant chemotherapy\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
After neoadjuvant chemotherapy\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (40)\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
4 (40)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age at surgery (years), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Age at surgery (years), median (range)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.7 (0.3-9.3)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.7 (0.3-9.3)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Biopsy only, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Biopsy only, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (31)\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4 (31)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: VDC-ICE, vincristine, doxorubicin, and cyclophosphamide
alternating with ifosfamide, carboplatin, and etoposide.

\textbf{TABLE 3.} Cycle specific toxicity\selectlanguage{english}
\begin{longtable}[]{@{}lll@{}}
\toprule
\begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
Cycles (n=87)\strut
\end{minipage} & \begin{minipage}[b]{0.30\columnwidth}\raggedright\strut
Cycles (n=87)\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
VDC\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
ICE\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Number of cycles received, \emph{n}\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
45\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
42\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Number of delayed cycles, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
7 (16)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
4 (10)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Delay reason, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Delayed count recovery\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
5 (71)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
2 (50)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Surgical recovery\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
1 (14)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
1 (25)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Other complication\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
1 (14)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0(0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Infection\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Unknown\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
1 (25)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Febrile neutropenia, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
20 (44)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
18 (43)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Acute kidney injury, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1 (2)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Minor electrolyte disturbance, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
2 (5)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Hemorrhagic cystitis, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
1 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Home hydration, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
0 (0)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
5 (12)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Unplanned hospital admission, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
22 (49)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
22 (52)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Reason for admission, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Febrile neutropenia\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
17 (77)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
16 (73)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Nausea/Vomiting/Dehydration\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
4 (18)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
5 (23)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
Other\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
11 (50)\strut
\end{minipage} & \begin{minipage}[t]{0.32\columnwidth}\raggedright\strut
8 (36)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
Unplanned ED/clinic visit, \emph{n} (\%)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
28 (62)\strut
\end{minipage} & \begin{minipage}[t]{0.30\columnwidth}\raggedright\strut
36 (86)\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: VDC, vincristine, doxorubicin, and cyclophosphamide; ICE,
ifosfamide, carboplatin, and etoposide; ED, emergency department.

\textbf{TABLE 4.} Grade 3 non-hematologic toxicities based on the common
terminology criteria for adverse events\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
& Total patients (n=14)\tabularnewline
\midrule
\endhead
Febrile neutropenia, \emph{n} (\%) & 13 (93)\tabularnewline
Anorexia/malnutrition, \emph{n} (\%) & 8 (57)\tabularnewline
Nausea/vomiting/dehydration, \emph{n} (\%) & 7 (50)\tabularnewline
Hepatotoxicity, \emph{n} (\%) & 2 (14)\tabularnewline
Hypotension, \emph{n} (\%) & 1 (7)\tabularnewline
Bacteremia, \emph{n} (\%) & 1 (7)\tabularnewline
Diarrhea, \emph{n} (\%) & 1 (7)\tabularnewline
Peripheral neuropathy, \emph{n} (\%) & 1 (7)\tabularnewline
\bottomrule
\end{longtable}

\selectlanguage{english}
\FloatBarrier
\end{document}

