A pilot study of chemotherapy intensification by adding vincristine, topotecan and cyclophosphamide to standard chemotherapy agents with an interval compression schedule in newly diagnosed patien...

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Content A PILOT STUDY OF CHEMOTHERAPY INTENSIFICATION BY ADDING
VINCRISTINE, TOPOTECAN AND CYCLOPHOSPHAMIDE TO STANDARD
CHEMOTHERAPY AGENTS WITH AN INTERVAL COMPRESSION SCHEDULE IN
NEWLY DIAGNOSED PATIENTS WITH LOCALIZED EWING SARCOMA FAMILY
OF TUMORS

by

Leo Mascarenhas

A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF SCIENCE
(CLINICAL AND BIOMEDICAL INVESTIGATIONS)

May 2008

Copyright 2008 Leo Mascarenhas

ii
Table of Contents

List of Tables iii

Abstract iv

Chapter 1: Goals and Objectives (Scientific Aims) 1
Background 1

Chapter 2: Eligibility Criteria 11

Chapter 3: Treatment Program 16
Dose Modification for Toxicity 34

Chapter 4: Evaluations and Data to be Accessioned 46
Criteria for Removal from Protocol Therapy and Off
Study Criteria 48

Chapter 5: Statistical Considerations 49

Chapter 6: Evaluation Criteria 55
Imaging Studies Required and Guidelines for Obtaining 58

Bibliography 61

Appendix A Sample Research Informed Consent 64
Appendix B Supportive Care 87

iii
List of Tables

Table 1 Threshold serum creatinine values based on age and
Gender 14

Table 2 Dose modifications for cyclophosphamide based on
renal function 37

Table 3 Chemotherapy dose modifications for hepatotoxicity 44

Table 4 Required and recommended observations during therapy 46

Table 5 Probability table of identifying accelerated strategy
as not feasible 53

Table 6 Response assessment criteria 57

Table 7 Required and recommended imaging 58

Table 7a At presentation and prior to local control 58

Table 7b After local control 59

Table 7c Surveillance on chemotherapy and end of therapy
Evaluations 59

Table 7d Surveillance post-chemotherapy 60

iv

Abstract

Intergroup Ewing sarcoma study INT-0091 demonstrated that a regimen of alternating
vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) was
superior to vincristine-doxorubicin-cyclophosphamide alone. The 5-drug regimen is the
North American standard therapy for localized Ewing sarcoma. COG-AEWS0031
investigated interval compression of the drug combination vs. standard chemotherapy for
localized Ewing sarcoma and showed that patients treated with interval compressed 5-drug
combination had a superior event free survival and overall survival when compared to
standard chemotherapy. Addition of new active drug combinations to standard chemotherapy
is a potential strategy to improve the outcome of patients with Ewing sarcoma. This pilot
clinical trial will investigate the addition of vincristine-topotecan-cyclophosphamide (VTC)
to a treatment protocol utilizing interval compression of VDC and IE for patients with
localized Ewing sarcoma family of tumors (ESFT). If feasible, this regimen will become the
experimental arm in a planned Group-wide phase III clinical trial in patients with Ewing
Sarcoma.

1
CHAPTER 1

GOALS AND OBJECTIVES (SCIENTIFIC AIMS)

Primary Objective
To assess the feasibility and safety of adding vincristine, topotecan and
cyclophosphamide (VTC) on an interval compressed schedule to a treatment
protocol utilizing interval compression of vincristine, doxorubicin,
cyclophosphamide (VDC) and ifosfamide, etoposide (IE) for patients with localized
Ewing sarcoma family of tumors (ESFT).

Secondary Objective
To estimate the event-free survival in this patient population treated with an interval
compression regimen that includes VTC.

BACKGROUND
Intergroup Ewing sarcoma study INT-0091 (CCG 7881, POG 8850) demonstrated
that a regimen of alternating VDC with IE was superior to VDC alone.
Dactinomycin was substituted for doxorubicin once a cumulative doxorubicin dose
of 375 mg/m
2
had been given. Patients received 17 courses of chemotherapy. Among
the 398 patients with non-metastatic disease the mean 5-year event free survival
(EFS) in the experimental arm was 69% ± 3% (198 patients) as compared with 54%
± 4% (200 patients) in the standard arm.
1
The 5-drug alternating combination
(without dactinomycin) has become the North American standard therapy for ESFT.

2
CCG 7942, POG-9354 evaluated the impact of increasing dose intensity of
chemotherapy by escalating the doses of the alkylating agents cyclophosphamide and
ifosfamide. Four hundred and seventy-eight patients met eligibility requirements;
231 received standard dose intensity and 247 received the experimental dose
intensified regimen. The overall 5-year EFS and overall survival (OS) rates for all
eligible patients were 70.4 ± 2.2% and 78.6 ± 2.0%, respectively. There was no
significant difference (p-value=0.7982) between patients treated with the standard
regimen (5-year EFS 70.8 ± 3.2%) compared to those treated with the dose-
intensified regimen (5-year EFS 70.1 ± 3.0%) (personal communication, Drs. Linda
Granowetter and Mark Krailo).

COG AEWS0031 (which closed to patient accrual in August 2005) investigated
interval compression of the 5-drug combination vs. standard chemotherapy for
localized Ewing sarcoma and showed comparable toxicity between both treatment
regimens. Five hundred and sixty four eligible patients were randomized between the
experimental every-2-week regimen and the standard every-3-week regimen.
Preliminary results of this study reveal that patients treated with the experimental
interval compressed 5-drug alternating combination had a superior EFS (4 year EFS:
76 vs. 65%, p=0.029) and OS (4 year OS: 91 vs. 85%, p= 0.026) when compared to
the standard 5-drug alternating combination administered every 3 weeks (personal
communication, Drs. Richard Womer and Mark Krailo). Thus, the 5-drug alternating

3
combination administered on an interval compressed schedule merits further
evaluation in future trials.

Another strategy to potentially improve outcome for these patients would be the
addition of new active drug combinations. The purpose of this trial is to investigate
whether we can continue to administer interval-compressed therapy when a
vincristine, topotecan and cyclophosphamide combination is added to the 5-drug
treatment backbone.

Rationale for the Vincristine, Topotecan and Cyclophosphamide (VTC) Combination

Cyclophosphamide in combination with topotecan has been studied in the pediatric
phase I setting, establishing a recommended dose of cyclophosphamide (250
mg/m
2
/dose) followed by topotecan (0.75 mg/m
2
/dose), each given as a 30-minute
infusion, daily for 5 days, followed by G-CSF on Day 6. The Pediatric Oncology
Group phase II study showed activity in recurrent or refractory rhabdomyosarcoma,
neuroblastoma and Ewing sarcoma. Responses were reported in 6/17 patients with
Ewing sarcoma. Hematopoietic toxicities were common but only 11% of 307 courses
were associated with Grade 3 or 4 infection.
2
Non-hematologic toxicities were rare.
Additional experience in the window setting in patients with disease metastatic at
initial diagnosis (P9457) yielded 21 subjects with partial responses (PR; 57%), 15
with stable disease (SD) and only 1 with progressive disease (PD) in 37 evaluable

4
patients treated with 1 (the patient with PD) or 2 cycles of topotecan-
cyclophosphamide. The predominant toxicity was hematologic. Non-hematopoietic
toxicities were rare.
3
Investigators from Germany confirm a similar response rate in
patients with recurrent Ewing sarcoma. Fifty-four patients (37 in first relapse)
received a median of 3 courses. Partial responses were observed in 16/49 (32.6%).
Thirteen (26.5%) had stable disease and 2 (4.1%) had mixed response.
4

In xenografts representing rhabdomyosarcoma, neuroblastoma and brain tumors, the
combination of topotecan and vincristine has greater than additive activity. The
schedule used was topotecan intravenously daily for 5 days and vincristine
intravenously every 7 days.
5
The combination of VTC has been tolerable in the
rhabdomyosarcoma intermediate risk study (D9803).

Based on these observations, the combination of topotecan-cyclophosphamide with
weekly vincristine is a good candidate for testing in previously untreated patients
with localized Ewing sarcoma.

Rationale for Dose Intensity

Clinical studies suggest that increasing the intensity of chemotherapy improves
prognosis in Ewing sarcoma. The second Intergroup Ewing Sarcoma Study (IESS-II)
for patients with non-metastatic disease at diagnosis or pelvic primary tumors

5
compared 2 regimens, each incorporating vincristine, doxorubicin, actinomycin-D,
and cyclophosphamide. The superior regimen, with 77% of patients surviving free of
disease at 5 years, was the one in which chemotherapy was delivered in intense
pulses; the inferior regimen (56% disease free survival [DFS]) gave lower doses of
the agents more continuously.
6
Though there were other differences between the 2
arms (particularly earlier introduction of doxorubicin in the intensive arm), the
results suggest that higher dose-intensity chemotherapy provides superior results in
Ewing sarcoma. A meta-analysis showed that the probability of survival was closely
related to the dose intensity of doxorubicin in the treatment program.
7

As detailed above, CCG 7942, POG-9354 explored increasing the dose intensity of
chemotherapy by escalating the doses of the alkylating agents, and although the
analysis (5-year EFS of 70.8% ± 3.2%) has not suggested a significant improvement
in EFS (personal communication, Drs. Linda Granowetter and Mark Krailo), the
experimental arm did not have excessive toxicity. Other solid malignancies in
pediatrics have benefited from dose intensification. Increased dose intensity in high-
risk neuroblastoma improved both EFS and OS on CCG 3891.
8
In addition, EFS was
significantly improved in patients with high risk germ cell tumors treated with high
dose cisplatin when compared to those treated with standard dose cisplatin on POG
9049/CCG 8882.
9

6
Dose intensification by escalating drug doses is limited by the toxicities of the agents
used. The advantage of dose intensification via interval compression is that it
provides a means of increasing the dose intensity of all drugs, without apparent
increases in toxicity. Decreasing the chemotherapy interval from three weeks to two
provides 33% dose intensification. Though this does not seem a huge increase, it
may be therapeutically significant. First, dose intensification involves all drugs,
rather than just the alkylating agents. Second, modest increases in dose intensity can
yield significant increases in response as suggested by a randomized study of 105
patients with small cell lung cancer where modest increases in the initial doses of
cisplatin and cyclophosphamide (30%) resulted in marked improvement in 2-year
disease free survival.
10

Several studies in adults with solid tumors have demonstrated the feasibility of
chemotherapy interval compression (also termed “acceleration”) using G-CSF or
GM-CSF.
11-16
A randomized 3-armed trial of adjuvant dose-dense versus
conventionally scheduled and sequential, versus concurrent combination
chemotherapy in women with node-positive primary breast cancer, resulted in
improved disease-free survival (p=0.01) and overall survival (p=0.013) in the
patients treated on the dose-dense chemotherapy schedule (every 2 weeks) when
compared with the other regimens.
14
Other trials in breast cancer patients have
demonstrated the feasibility of administering dose-dense chemotherapy without
improving response rate or efficacy.
11,15
An additional two randomized phase III

7
trials of dose-dense chemotherapy in patients with Small Cell Lung Cancer did not
result in improved survival.
13,16
However, the response rate was higher in the
experimental arm of 1 study
16
while the experimental arm led to shorter duration of
treatment and less neutropenic sepsis in the other study.
13

Interval compression was first attempted in children with a weekly “rapid VAC”
protocol using weekly vincristine, doxorubicin, and cyclophosphamide in children
with rhabdomyosarcoma; this 1981-89 study was conducted without growth
factors.
17
The results of this 5-month regimen were similar to those achieved with the
1- to 2-year regimens then in general use. There is also some evidence that giving
chemotherapy more frequently can improve survival in children. In the CCG-2891
study of acute myeloid leukemia, patients were randomly assigned to induction
chemotherapy with “standard timing” (2 weeks between induction cycles, or when
count recovery occurred) or “intensive timing” (10 days between cycles, regardless
of counts). The patients assigned to intensive timing had a significantly improved
survival, whether or not they subsequently underwent marrow transplantation.
18

Limits to both doses and acceleration exist. A study of every-14-day chemotherapy
using cyclophosphamide, etoposide, and fluorouracil for advanced breast cancer,
which escalated chemotherapy doses with successive cohorts of patients,
demonstrated that the treatment intervals lengthened as doses rose.
19
Another study
used constant doses of epirubicin and cyclophosphamide for advanced breast cancer,

8
and trimmed the treatment interval between patient cohorts. When the treatment
interval reached 13 days, mucositis and dermatitis became severe, and plans to
proceed to a 10-day interval were abandoned.
20
The majority of cancers in adults are
relatively chemotherapy insensitive. This may explain the apparent lack of
improvement in outcome in most adult trials using dose-compressed therapy.

A previous pilot study has tested the alternating combination of vincristine,
doxorubicin, cyclophosphamide (VDC) and ifosfamide, etoposide (IE), in sarcomas
using interval dose compression.
21
In that study, 71 patients were treated with
chemotherapy cycles every 14 days or upon absolute neutrophil count and platelet
count recovery. Toxicity was modest and EFS comparable to other clinical trials.
Additionally, the recently closed COG study, AEWS0031, comparing interval dose
compression with VDC/IE to standard timing in patients with non-metastatic Ewing
sarcoma, has had comparable levels of toxicity in both arms of the study (personal
communication, Drs. Richard Womer and Mark Krailo). The mean cycle length for
the interval compression regimen was 5.7 days shorter than the standard regimen.
When the first 3 courses alone were considered, similar results were noted. When
each course was considered as an independent observation and the Wilcoxon test
was used to assess differences between the distributions of cycle length, the
associated p-value was less than 0.001. This recent experience with AEWS0031 is
further evidence that combinations of VDC and IE can be alternated every 2 weeks
in an interval compression schedule without increased toxicity in the co-operative

9
group setting. Further, patients treated with the experimental interval compressed 5-
drug alternating combination had a superior EFS at 4 years when compared to the
standard 5-drug alternating combination administered every 3 weeks (76 vs. 65%,
p=0.029).

AEWS0031 was a unique study in that it evaluated dose intensification via interval
compression (it provided a dose-dense schedule without modifying the standard
chemotherapy doses). This pilot study, AEW07P1, will investigate interval
compression using standard doses of chemotherapy with the addition of vincristine,
topotecan and cyclophosphamide to the five drug alternating combination of VDC-
IE.

Development Plans

The next localized Ewing sarcoma study (AEWS0531) will evaluate whether the
addition of VTC improves outcome for patients with localized Ewing sarcoma. Since
the experimental arm of AEWS0031 utilizing interval-compressed therapy appears to
be superior, the 5-drug regimen will be administered every 2 weeks on AEWS0531.
The purpose of this pilot is to determine whether it is feasible to administer VTC
combined with VDC-IE every 2 weeks. If this pilot proves feasible then the
AEWS0531 protocol will have chemotherapy on both the standard and experimental
arms administered every 2 weeks. If this pilot proves unfeasible then the VTC cycles
in the experimental arm of AEWS0531 will be administered every 3 weeks while the

10
rest of the cycles are administered every 2 weeks. Thus, this pilot seeks feasibility
data of interval compressed VTC+VDC-IE.

11

CHAPTER 2
ELIGIBILITY CRITERIA

Study Enrollment
Patients may be enrolled on the study once all eligibility requirements for the study
have been met.

Timing
Patients must be enrolled before treatment begins. The date protocol therapy is
projected to start must be no later than five (5) calendar days after the date of study
enrollment.

Important Pretreatment Information-Venous Access
In order to facilitate safe administration of the required chemotherapy agents and
support medications. Placement of a central venous access device, preferrably double
lumen, is strongly recommended. This will often require a surgical procedure under
general anesthesia, for which separate consent should be obtained.

Patient Criteria:

Age
Patients must be less than 31 years of age.

12
Diagnosis
Patients with newly diagnosed, biopsy confirmed, extracranial, non-metastatic Ewing
sarcoma or PNET of bone or soft tissue are eligible for this study.

Patients must have no evidence of metastatic disease defined as lesions which are
discontinuous from the primary tumor, are not regional lymph nodes and do not
share a body cavity with the primary tumor.

Patients must be free of evidence of metastatic lung disease as defined by CT scan:
• One pulmonary nodule > 1 cm in diameter, or more than one nodule > 0.5 cm
diameter are considered evidence of pulmonary metastasis; patients with such
nodules are not eligible for this study unless the nodules are resected and are
NOT metastatic Ewing sarcoma.
• Solitary nodules of 0.5 to 1.0 cm or multiple nodules of 0.3 to 0.5 cm are not
considered metastatic unless biopsy proven. Patients with biopsy proven lung
metastases are not eligible.
• Solitary nodules < 0.5 cm or multiple nodules < 0.3 cm are not considered
clear evidence of lung disease and such patients are eligible for the study;
biopsy is not required. If biopsies are obtained and are positive, the patient is
not eligible for the study.

13
For the purpose of this study, chest wall tumors with ipsilateral pleural effusions,
ipsilateral positive pleural fluid cytology or ipsilateral pleural based secondary tumor
nodules will be considered to have localized disease and are eligible for this study.
Patients with contralateral pleural effusions or pleural nodules are not eligible.

Patients with regional lymph node involvement, based on clinical suspicion or
confirmed by biopsy, are eligible. Patients with distant lymph node metastases are
not eligible.

Patients with tumors arising in the bony skull (extra-dural) are eligible for this study.
Patients whose tumors arise in the intra-dural soft tissue are not eligible. Patients
with tumors arising in the intra-dural region of the spine are not eligible.

Pathologic Criteria
Patient eligibility will be based on a diagnosis of Ewing sarcoma or PNET by
institutional pathologist.

Performance Level
Patients must have a performance status of 0, 1, or 2. The Lansky performance score should
be used for patients < 16 years and the Karnofsky performance score for patients ≥ 16
years.

14
Prior Therapy
No chemotherapy or radiation therapy prior to study enrollment is allowed. Patients
must have had only a biopsy of the primary tumor without an attempt at complete or
partial resection. Patients will still be eligible if an unplanned excision was attempted
or accomplished as long as adequate imaging was obtained prior to surgery, but must
be considered incompletely resected and will require further local control.

Organ Function Requirements:
Adequate Renal Function Defined As:
- Creatinine clearance or radioisotope GFR ≥ 70 mL/min/1.73 m
2
or
- A serum creatinine based on age/gender as follows:
Table 1: Threshold serum creatinine values based on age and gender.
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

Adequate liver function defined as:
- Total bilirubin ≤ 1.5 x upper limit of normal (ULN) for age, and
- SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for
age.

15
Adequate cardiac function defined as:
- Shortening fraction of ≥ 27% by echocardiogram, or
- Ejection fraction of ≥ 50% by radionuclide angiogram (MUGA).

Exclusion Criteria
Pregnancy or breast-feeding: Pregnant female patients are ineligible since fetal toxicities and
teratogenic effects have been noted for several of the study drugs. Pregnancy tests with a
negative result must be obtained in all post-menarchial females. Males and females of
reproductive potential may not participate unless they have agreed to use an effective
contraceptive method. Lactating females must agree that they will not breastfeed a child while
on this study.

Regulatory
All patients and/or their parents or legal guardians must sign a written informed consent
(Appendix A).

All institutional, FDA, and NCI requirements for human studies must be met.

16
CHAPTER 3
TREATMENT PROGRAM

Overview of Treatment Plan

Patients should not have planned surgical resections prior to chemotherapy. If a
patient has a (presumably small) soft tissue mass that was not expected to be
malignant and was therefore resected in a “non-oncologic” manner, further local
therapy will be required. This applies even if the microscopic margin is thought to be
clear. Local control decisions should be made as though the initial procedure was the
equivalent of a large biopsy.

Protocol therapy will consist of Induction, Local Control and Continuation therapy.
All patients will receive a total of 17 cycles of chemotherapy; each cycle will be of 2
weeks duration. Induction consists of six cycles (12 weeks) of chemotherapy and
will be delivered prior to local control therapy which may involve surgery and/or
radiation therapy. Continuation therapy will consist of 11 cycles (22 weeks) of
chemotherapy.

Local therapy planning with a surgical and radiation oncology team should be
initiated at diagnosis. Surgery should be scheduled for the time of recovery from the
sixth cycle of induction chemotherapy - usually at Week 13. If radiation therapy is to
follow surgery, radiation therapy should be scheduled to start at Week 15 or as soon
as recovery from surgery permits. Patients who are to be treated with planned

17
radiation followed by consideration of later excision should be treated with radiation
during Weeks 13-19, and the surgery should be performed after recovery from Cycle
11 of chemotherapy.

When surgery is performed, the next cycle of chemotherapy should be given as soon
as possible post-operatively (usually by 10 days to 2 weeks following the surgery)
unless there are exceptional circumstances. The passing of more than six weeks
between chemotherapy cycles for reasons other than severe chemotherapy toxicity
should be avoided.

If radiation is being used as the primary modality of local control or will be given
pre-operatively then continuation chemotherapy should be initiated concurrently with
the radiation therapy, ie, both radiation and chemotherapy Cycle 7 should begin at
chronological Week 13. The subsequent ifosfamide-etoposide chemotherapy, Cycles
8 and 9, should be given as usual (at two week intervals). Doxorubicin is not
scheduled during the period in which radiation is planned and should not be given
during radiation treatment. Administration of topotecan concurrently with radiation
is allowed.

There are four reporting periods: (1) Weeks 1-12, (2) Weeks 13-22, (3) Weeks 23-
28, and (4) Weeks 29-37.

18
General Approach to Primary Tumor Treatment (Local Control)
This study requires definitive treatment of the primary tumor with complete surgical
excision, a combination of surgical excision and radiation therapy for microscopic
residual disease, or full-dose radiation therapy. A multidisciplinary approach to
primary tumor treatment involving the oncologist, the radiation oncologist, and the
surgeon is indispensable, and planning should begin immediately upon diagnosis.
The guiding principle for local control should be to eradicate the primary tumor and
avoid local recurrence with the least amount of functional loss. This will require
careful consultation between the orthopedic or surgical oncologist and the radiation
oncologist.

Recent experience indicates that most patients will be treated with surgical excision
alone or surgical excision preceded or followed by radiation therapy.

Primary Tumor Treatment Modalities

Surgery Only
All patients who respond to induction chemotherapy should be considered for
surgical excision if it is believed that the lesion can be resected with negative
margins and a reasonable functional result. If surgical expertise is not available at a
given institution it is strongly suggested that consultation be made with an
experienced orthopedic or surgical oncologist at another institution. Patients with

19
complete resections with adequate margins (defined as a minimum of 2 mm [fascial
planes] or 5 mm [fat and muscle planes] or 1 cm [bone], see Section 13 for more
information) will not receive radiation therapy. Patients with unresectable lesions or
inadequate margins after surgery will receive radiation therapy. Patients with bulky
lesions in difficult sites who do not have a good clinical and radiographic response to
induction chemotherapy may be treated with radiotherapy to the primary, and then
re-evaluated for possible resection of the involved site following radiation, after
recovery from Cycle 11 of chemotherapy. Expert opinions from surgical/orthopedic
oncology and radiation oncology may be obtained to assist with this situation.
Amputation should be reserved for selected situations and should be discussed with
an experienced orthopedic or surgical oncologist.

Radiation Therapy Only
Candidates for radiotherapy alone will include patients with bulky lesions in
surgically difficult sites such as the spine, skull and periacetabular pelvis, patients
with a poor response to induction chemotherapy, or those patients in whom surgery
would result in unacceptable functional results. Sites which, if removed, would result
in significant impairment of function include the skull, facial bones, vertebrae and
pelvic bones about the acetabulum. In some cases, resection even in these sites may
be feasible in combination with radiation therapy, and decisions regarding a specific
patient must be individualized.

20
Patients who are to be treated with radiotherapy alone should be treated with
radiation starting at Week 13.

Surgery Plus Radiation Therapy
Most patients will have either surgery alone, surgery with radiation therapy for close
margins, or radiation therapy alone. However, many orthopedic and surgical
oncologists prefer to combine marginal resections with either pre-operative or post-
operative radiation routinely, especially for “bulky” tumors in difficult sites. While
avoiding radiation completely appears to offer some advantage, for example
decreasing the risk of secondary sarcoma, if adequate local control is achieved, a
combined approach appears to be a reasonable alternative. However, this approach
may result in considerable delays in chemotherapy: thus the benefits must be
weighed against risk in each patient. This approach is most appropriate for large
bulky primaries, greater than 10 cm in maximal dimension, or when the lesion has
responded but remains unresectable after induction chemotherapy. The use of
postoperative radiotherapy may permit use of a more limited surgical procedure, and
will be administered in any patient who has residual disease, or inadequate surgical
margins. The decision regarding whether the radiation will precede or follow the
resection will be left to the treating team. This should be planned in advance with the
surgical oncologist and the radiation oncologist.

21
When surgery is done first, followed by radiation therapy, surgery should occur as
soon as possible after recovery from Cycle 6 of chemotherapy. Radiation therapy
should begin as soon as feasible thereafter.

Patients who are to be treated with planned radiation, followed by consideration of
later excision, should be treated with radiation during Weeks 13-19 and the surgery
should be performed after recovery from Cycle 11 of chemotherapy.

Patients with microscopic residual disease after planned pre-operative radiation
therapy will receive additional radiation.

Concomitant Medications

No other cancer chemotherapy or immunomodulating agents (including steroids
unless used as an antiemetic) will be used.

Strong inhibitors of cytochrome P450 3A4 are known to alter vincristine
metabolism, leading to increased vincristine neurotoxicity. Strong inhibitors or
stimulators of cytochrome P450 3A4, including azole anti-fungals (voriconazole,
itraconazole, ketoconazole, fluconazole), rifampin, phenytoin, phenobarbital,
carbamazepine, and St. John’s wort, should all be avoided or used with great caution.

22
A more complete list of drugs that are metabolized by cytochrome P450 isoform is
available via the link below. Drug names are hyperlinks to specific journal
references:
http://medicine.iupui.edu/flockhart/

Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes and general
supportive care are to be used as necessary (see Appendix B).

23

Figure: Treatment Schema

INDUCTION CONTINUATION
Cycle Week Drugs

Cycle Week Drugs

1 VTC
250
15 VTC
250 1
2 V
7
16 V
3 IE 17 IE 2
4
8
18
5 VDC
1200
19 IE 3
6 V
9
20
7 IE 21 VTC
250 4
8
10
22 V
9 VTC
250
23 VDC
1200 5
10 V
11
24 V
11 VDC
1200
25 IE 6
12 V
12
26
13 27 VD#C
1200
Evaluations
Local
Control
14

13
28 V
29 VTC
250
14
30 V
31 IE 15
32
33 VD#C
1200
16
34 V
35 IE 17
36
NOTE: If radiation is the primary local
control measure or will be given pre-
operatively then continuation chemotherapy
should be initiated concurrently with the
radiation therapy, i.e., both radiation and
chemotherapy Cycle 7 should begin at
chronological Week 13.
Evaluations
End of Therapy

VTC
250
V = Vincristine
T = Topotecan
C
250
= Cyclophosphamide

IE
I = Ifosfamide
E = Etoposide

VDC
1200
V = Vincristine.
D = Doxorubicin
C
1200
= Cyclophosphamide

# = Dexrazoxane

Note: Filgrastim (G-CSF) use between cycles is required for interval compression.

24

Administration Schedules

Administration Schedule for Induction Therapy (Weeks 1-12)
Criteria to start first cycle: ANC ≥ 750/µL and platelets ≥ 75,000/µL (without
transfusion).
Criteria to start subsequent cycles: ANC ≥ 750/µL and platelet count ≥ 75,000/µL
post nadir (without transfusion). The ANC often falls after discontinuing myeloid
growth factor support (filgrastim). If the ANC has risen to ≥ 750/µL after the nadir
but then falls the next cycle can be given despite ANC < 750/µL. (Note: for children
less than 1 year of age or weighing less than 10 kilograms, chemotherapy should be
calculated by weight rather than by surface area. Dose/kilogram = dose/meter
2

divided by 30).

Vincristine (VCR)
Administer by IV push over 1 minute on Day 1 of Weeks 1, 2, 5, 6, 9, 10, 11 and 12.
VCR dose is 1.5 mg/m
2
/dose (maximum dose 2 mg).

Topotecan (TOPO)
Administer by IV infusion over 30 minutes on Days 1-5 of Weeks 1 and 9.
TOPO dose is 0.75 mg/m
2
/dose.
Reconstitute to a concentration of 1 mg/mL and further dilute in 50-250 mL of D5W
or NS.

25
Cyclophosphamide (CPM)
(Note that the VDC and the VTC combinations involve a different dose of CPM).

C
250
– dose administered during cycles of VTC
Administer by IV infusion over 1 hour on Days 1-5 of Weeks 1 and 9.
C
250
dose is 250 mg/m
2
/dose.
Cyclophosphamide should be reconstituted to a concentration of 20 mg/mL and may
be administered as undiluted drug concurrently with post hydration or further diluted
in 50, 100, 250, or 500 mL of fluid.
Fluids: Suggest pre-hydration with 500 mL/m
2
over 30 minutes and administer 1500
mL/m
2
/24 hours IV/PO post cyclophosphamide. Parenteral fluids should contain at
least 0.45% NaCl.

C
1200
– dose administered during cycles of VDC
Administer by IV infusion over 1 hour on Day 1 of Weeks 5 and 11.
C
1200
dose is 1200 mg/m
2
/dose.
Cyclophosphamide should be reconstituted to a concentration of 20 mg/mL and may
be administered as undiluted drug concurrently with post hydration or further diluted
in 50, 100, 250, or 500 mL of fluid.
Mesna must be administered in conjunction with C
1200

Fluids: Suggested pre-hydration on Day 1 is 200 mL/m
2
/hour. Achieve urine specific
gravity ≤ 1.010 prior to start of cyclophosphamide. Hydration after

26
cyclophosphamide is 3000 mL/m
2
/day (125 mL/m
2
/hour) using fluid containing at
least 0.45% NaCl.

Ifosfamide (IFOS)
Administer by IV infusion over 1 hour on Days 1-5 of Weeks 3 and 7.
IFOS dose is 1800 mg/m
2
/dose.
Reconstitute to a concentration of 50 mg/mL, further dilute in a convenient volume
of D5W or NS to a final concentration between 0.6-20 mg/mL.
Mesna must be administered in conjunction with IFOS

Fluids: Suggested pre-hydration on Day 1 is 200 mL/m
2
/hour. Achieve urine specific
gravity ≤ 1.010 prior to start of ifosfamide. Hydration after ifosfamide is 3000
mL/m
2
/day (125 mL/m
2
/hour) using fluid containing 0.45% NaCl or 0.9% NaCl.

Etoposide (ETOP)
Administer by IV infusion over 1 hour on Days 1-5 of Weeks 3 and 7.
ETOP dose is 100 mg/m
2
/dose.
Administer at a final concentration ≤ 0.4 mg/mL in D5W or NS (use standard
dilution volumes of 50, 100, 250, 500, 1000 mL); avoid use of large volumes of
D5W due to potential development of hyponatremia. Slow rate of administration if
hypotension occurs. Use in-line filter during infusion secondary to precipitate
formation risk.

27
Doxorubicin (DOXO)
Administer by IV infusion over 15 minutes on Days 1 and 2 of Weeks 5 and 11.
DOXO dose is 37.5 mg/m
2
/dose on each day.
Administer at a final concentration of 2 mg/mL. Avoid extravasation.
See Section 5.3.2 for dose modifications regarding the use of dactinomycin in place
of doxorubicin.

Mesna (MESNA)
When administered intravenously, the total daily mesna dose is equal to 60% of the
daily ifosfamide or cyclophosphamide (C
1200
) dose and is administered in 3 divided
doses diluted to a concentration of 20 mg/mL. (For example, if the dose of
ifosfamide were 1 g/m
2
, the three IV mesna doses would be 200 mg/m
2
each.) Initial
bolus dose of mesna may be administered before or at the same time as the
ifosfamide or cyclophosphamide; subsequent doses are given 4 and 8 hours after the
start of ifosfamide or cyclophosphamide. Mesna can also be administered as a
continuous IV infusion. Dilute in D5W or NS to a convenient volume (e.g., 120-240
mL/day). The continuous infusion should be started at the same time as the
ifosfamide or cyclophosphamide and finish no sooner than 8 hours after the end of
the ifosfamide or cyclophosphamide infusion.
Patients able to tolerate oral mesna may receive the second and/or the third dose(s)
by mouth at a dosage of 40% of the oxazaphospharine (cyclophosphamide or
ifosfamide) dose. The first dose of mesna should be given intravenously. The oral
dose of mesna is twice the IV dose and each oral dose should be given 2 hours earlier

28
than an intravenous dose would be given. For example, if the dose of ifosfamide is 1
g/m
2
, the first MESNA dose would be 200 mg/m
2
IV at the time of the ifosfamide
dose, followed by oral doses of 400 mg/m
2
at hours 2 and 6, rather than at hours 4
and 8.

Mesna with IFOS
Administer MESNA by IV infusion or IV/PO on Days 1-5 of Weeks 3 and 7.

Mesna with C
1200
Administer MESNA by IV infusion or IV/PO on Day 1 of Weeks 5 and 11.

Filgrastim (G-CSF)
Administer subcutaneously beginning 24-36 hours after the last dose of
chemotherapy. Continue at least 7 days or until the post-nadir absolute neutrophil
count is ≥ 750/μL, whichever comes last. G-CSF should be stopped a minimum of 24
hours prior to the administration of the next chemotherapy cycle.
G-CSF dose is 5 micrograms/kg/dose (maximum 300 micrograms).
(Note: Use of Neulasta (pegfilgrastim) or GM-CSF (sargramostim) is not permitted)

Local control (Weeks 13 and 14) will follow Induction.

29
Administration Schedule for Continuation Therapy (Weeks 15-36)
Criteria to start each cycle: ANC ≥ 750/µL and platelet count ≥ 75,000/µL post nadir
(without transfusion). The ANC often falls after discontinuing myeloid growth factor
support (filgrastim). If the ANC has risen to ≥ 750/µL after the nadir but then falls
the next cycle can be given despite ANC < 750/µL.

(Note: for children less than 1 year of age or weighing less than 10 kilograms,
chemotherapy should be calculated by weight rather than by surface area.
Dose/kilogram = dose/meter
2
divided by 30)

Vincristine (VCR)
Administer by IV push over 1 minute on Day 1 of Weeks 15, 16, 21-24, 27-30, 33
and 34.
VCR dose is 1.5 mg/m
2
/dose (maximum dose 2 mg).
Topotecan (TOPO)
Administer by IV infusion over 30 minutes on Days 1-5 of Weeks 15, 21 and 29.
TOPO dose is 0.75 mg/m
2
/dose.
Reconstitute to a concentration of 1 mg/mL and further dilute in 50-250 mL of D5W
or NS.

Cyclophosphamide (CPM)
(Note that the VDC and the VTC combinations involve a different dose of CPM).

30

C
250
– dose administered during cycles of VTC
Administer by IV infusion over 1 hour on Days 1-5 of Weeks 15, 21 and 29.
C
250
dose is 250 mg/m
2
/dose.
Cyclophosphamide should be reconstituted to a concentration of 20 mg/mL and may
be administered as undiluted drug concurrently with post hydration or further diluted
in 50, 100, 250, or 500 mL of fluid.
Fluids: Suggest pre-hydration with 500 mL/m
2
over 30 minutes and administer 1500
mL/m
2
/24 hours
IV/PO post cyclophosphamide. Parenteral fluids should contain at least 0.45% NaCl.

C
1200
– dose administered during cycles of VDC
Administer by IV infusion over 1 hour on Day 1 of Weeks 23, 27 and 33.
C
1200
dose is 1200 mg/m
2
/dose.
Cyclophosphamide should be reconstituted to a concentration of 20 mg/mL and may
be administered as undiluted drug concurrently with post hydration or further diluted
in 50, 100, 250, or 500 mL of fluid.
Mesna must be administered in conjunction with C
1200
.
Fluids: Suggested pre-hydration on Day 1 is 200 mL/m
2
/hour. Achieve urine specific
gravity ≤ 1.010 prior to start of cyclophosphamide. Hydration after
cyclophosphamide is 3000 mL/m
2
/day (125 mL/m
2
/hour) using fluid containing at
least 0.45% NaCl.

31
Ifosfamide (IFOS)
Administer by IV infusion over 1 hour on Days 1-5 of Weeks 17, 19, 25, 31 and 35.
IFOS dose is 1800 mg/m
2
/dose.
Reconstitute to a concentration of 50 mg/mL, further dilute in a convenient volume
of D5W or NS to a final concentration between 0.6-20 mg/mL.
Mesna must be administered in conjunction with IFOS (see Section 4.2.2.8).
Fluids: Suggested pre-hydration on Day 1 is 200 mL/m
2
/hour. Achieve urine specific
gravity ≤ 1.010 prior to start of ifosfamide. Hydration after ifosfamide is 3000
mL/m
2
/day (125 mL/m
2
/hour) using fluid containing 0.45% NaCl or 0.9% NaCl.

Etoposide (ETOP)
Administer by IV infusion over 1 hour on Days 1-5 of Weeks 17, 19, 25, 31 and 35.
ETOP dose is 100 mg/m
2
/dose.
Administer at a final concentration ≤ 0.4 mg/mL in D5W or NS (use standard
dilution volumes of 50, 100, 250, 500, 1000 mL); avoid use of large volumes of
D5W due to potential development of hyponatremia. Slow rate of administration if
hypotension occurs. Use in-line filter during infusion secondary to precipitate
formation risk.

Doxorubicin (DOXO)
Administer by IV infusion over 15 minutes on Days 1 and 2 of Weeks 23, 27 and 33.

32
DOXO dose is 37.5 mg/m
2
/dose on each day.
Administer at a final concentration of 2 mg/mL. Avoid extravasation.

Dexrazoxane (DEXRA)
Administer by IV push immediately prior to doxorubicin on Days 1 and 2 of Weeks
27 and 33. (Note: the elapsed time from the beginning of the dexrazoxane dose to the
end of the anthracycline infusion should be 30 minutes or less).
DEXRA dose is 375 mg/m
2
/dose (i.e., 10 mg of DEXRA for every mg of
doxorubicin).
Reconstitute with special diluent provided to concentration of 10 mg/mL.

Mesna (MESNA)
When administered intravenously, the total daily mesna dose is equal to 60% of the
daily ifosfamide or cyclophosphamide (C
1200
) dose and is administered in 3 divided
doses diluted to a concentration of 20 mg/mL. (For example, if the dose of
ifosfamide is 1 g/m
2
, the three IV mesna doses would be 200 mg/m
2
each.) Initial
bolus dose of mesna may be administered before or at the same time as the
ifosfamide or cyclophosphamide; subsequent doses are given 4 and 8 hours after the
start of ifosfamide or cyclophosphamide. Mesna can also be administered as a
continuous IV infusion. Dilute in D5W or NS to a convenient volume (e.g., 120-240
mL/day). The continuous infusion should be started at the same time as the
ifosfamide or cyclophosphamide and finish no sooner than 8 hours after the end of
the ifosfamide or cyclophosphamide infusion.

33

Patients able to tolerate oral mesna may receive the second and/or the third dose(s)
by mouth at a dosage of 40% of the oxazaphospharine (cyclophosphamide or
ifosfamide) dose. The first dose of mesna should be given intravenously. The oral
dose of mesna is twice the IV dose and each oral dose should be given 2 hours earlier
than an intravenous dose would be given. For example, if the dose of ifosfamide is 1
g/m
2
, the first mesna dose would be 200 mg/m
2
IV at the time of the ifosfamide dose,
followed by oral doses of 400 mg/m
2
at hours 2 and 6, rather than at hours 4 and 8.

Mesna with IFOS
Administer MESNA by IV infusion or IV/PO on Days 1-5 of Weeks 17, 19, 25, 31
and 35.

Mesna with C
1200
Administer MESNA by IV infusion or IV/PO on Day 1 of Weeks 23, 27 and 33.

Filgrastim (G-CSF)
Administer subcutaneously beginning 24-36 hours after the last dose of
chemotherapy. Continue at least 7 days or until the post-nadir absolute neutrophil
count is ≥ 750/μL, whichever comes last. G-CSF should be stopped a minimum of 24
hours prior to the administration of the next chemotherapy cycle.
G-CSF dose is 5 micrograms/kg/dose (maximum 300 micrograms).
Note: Use of Neulasta (pegfilgrastim) or GM-CSF (sargramostim) is not permitted.

34
DOSE MODIFICATION FOR TOXICITY

Slow Blood Count Recovery

Recovery of absolute neutrophil count (ANC: neutrophils + bands) to ≥ 750/µL, and
platelet count to ≥ 75,000/µL is required at the start of each myelosuppressive cycle.
The ANC often falls after discontinuing myeloid growth factor support (filgrastim).
If the ANC has risen to ≥ 750/µL after the nadir but then falls, the next cycle can be
given despite ANC < 750/µL. If a cycle is delayed for more than 7 days, the next
time the chemotherapy combination causing the delay is administered doses of
myelosuppressive agents (doxorubicin, cyclophosphamide, etoposide, ifosfamide and
topotecan) should be reduced by 25%. If cycles are still delayed, a further 25%
reduction in dose may be made. Re-escalation should be attempted if subsequent
cycles do not result in treatment delay. Vincristine doses at weeks where vincristine
is given alone should be given regardless of blood counts.

Renal Toxicity

Ifosfamide
Renal toxicity is the primary, long-term dose-limiting side effect of ifosfamide.
Available information indicates that the renal injury produced by ifosfamide may be
permanent, and in some cases progressive. Renal irradiation, young age (< 3 years of
age), and absence of one kidney are risk factors for severe renal toxicity. The
elements below define incomplete and significant Fanconi’s syndrome for the

35
purposes of this study. In the event a patient appears to have evidence of Fanconi’s
syndrome, the investigator may consider evaluation as detailed below and consider
modifying therapy as detailed below.

Elements of Fanconi Syndrome include:
1. Renal phosphorus wasting with hypophosphatemia (serum phosphate < 2.5
mg/dL= 0.8 mmol/L).
2. Renal bicarbonate wasting with acidosis (Bicarbonate < 16).
3. Renal potassium wasting with hypokalemia (< 3.0 mEq/L).
4. 1+ glycosuria with serum glucose < 150 mg/dL.
5. Proteinuria: a ratio of urine protein: urine creatinine > 0.2 occurring in the
absence of significant malnutrition and acidosis due to sepsis/infection.

Incomplete Fanconi Syndrome, with only one or a few of these elements, is
common. Over time, these abnormalities may resolve, remain static, or progress.

For the purposes of this study, significant Fanconi Syndrome will be defined as:
1. GFR is < 50 mL/min/1.73m
2
, not due to other causes such as aminoglycoside
toxicity, amphotericin B, etc., in the presence of mineral/electrolyte wasting,
OR
2. GFR is any level, but there is significant evidence of persistent Renal Tubular
Acidosis (RTA) as evidenced by serum bicarbonate less than 16 mmol/L and

36
serum phosphate ≤ 2 mg/dL (or ≤ 0.6 mmol/L) without supplementation on
measurements taken before the next ifosfamide cycle.

Modify therapy as follows:
Delete ifosfamide from all subsequent cycles and substitute cyclophosphamide 440
mg/m
2
per day with MESNA uroprotection for 5 days to be given together with 5
days of etoposide. This schedule of fractionated cyclophosphamide has previously
been used in National Wilms Tumor Trial V, Regimen I.

Etoposide
If Grade 2 or greater renal toxicity (creatinine > 1.5 X ULN) occurs, nephrotoxic
agents should be discontinued, chemotherapy held and renal function tests repeated
in one week. If toxicity persists a GFR or creatinine clearance should be obtained.
The following initial dose modification should be considered based on measured
creatinine clearance: for CrCl > 50 mL/min/1.73m
2
give full dose, for CrCl of 15-
50 mL/min/1.73m
2
give 75% of the dose (a 25% dose reduction). Etoposide should
be held if CrCl < 15 mL/min/1.73m
2
.

Cyclophosphamide
If Grade 2 or greater renal toxicity (creatinine >1.5 X ULN) occurs, nephrotoxic
agents should be discontinued, cyclophosphamide, since it is subject to renal
clearance, should be held and renal function repeated in one week. If estimated

37
creatinine clearance (eGFR) drops by > 33% (1/3) from the eGFR at study baseline
or if the eGFR drops into the abnormal range, cyclophosphamide will require dose
modifications. Prior to dose adjustment the local investigator should confirm the
subject was well hydrated when renal chemistries were obtained and a validated 24-
hour creatinine clearance or a radionuclide GFR should be obtained.

The following initial dose modification should be instituted:

Table 2: Dose modifications for cyclophosphamide based on renal function.

Renal function Cyclophosphamide dose
If drop in eGFR < 33% AND CrCl > 40
mL/min/1.73m
2
Full dose
If drop in eGFR > 33% BUT CrCl > 40
mL/min/1.73m
2
90% dose
If drop in eGFR > 33% BUT CrCl < 40 but > 10
mL/min/1.73m
2
50% dose
If CrCL < 10 mL/min/1.73m² Withhold until toxicity
resolves

Topotecan
If Grade 2 or greater renal toxicity (creatinine > 1.5 X ULN) occurs, nephrotoxic
agents should be discontinued, chemotherapy held and renal function tests repeated
in one week. If toxicity persists a GFR or creatinine clearance should be obtained.
The following initial dose modification should be considered based on measured
creatinine clearance: for CrCl > 40 mL/min/1.73m
2
give full dose, for CrCl of 20-

38
40 mL/min/1.73m
2
give 50% of the dose (a 50% dose reduction). Topotecan should
be held if CrCL < 20 mL/min/1.73m
2
.

Cardiac Toxicity

Monitoring
An electrocardiogram and echocardiogram with determination of shortening fraction,
or radionuclide angiogram for ejection fraction should be performed before
treatment, prior to every other doxorubicin cycle until a dose of 300 mg/m
2
is
reached, prior to every doxorubicin cycle once the cumulative dose exceeds 300
mg/m
2
, and at the completion of therapy. Use the same test each time for consistency
in evaluation.

Abnormalities
If prolongation of the QTc interval (> 0.44 sec), a decrease in the shortening fraction
to < 27 percent, or a decrease in the ejection fraction to < 45 percent is observed, the
doxorubicin-containing chemotherapy should be postponed one week, any existing
malnutrition corrected and the tests repeated. If the abnormalities persist,
doxorubicin should be permanently discontinued. Substitute Dactinomycin 0.045
mg/kg/day (max dose 2.5 mg) for 1 day, IV slow push on Day 1 only.

39
Neurological Toxicity

Neurological toxicity can result from two of the agents used in this study, vincristine
and ifosfamide.

Vincristine Neuropathy
Vincristine neurotoxicity may occur more frequently on this trial as a result of the
increased exposure to vincristine.

Grades 1 and 2 neurotoxicity requires no dose modification. For Grades 3 and 4
(interfering with activities of daily living) hold until symptoms decrease to Grade 1
(present on exam/testing but not symptomatic) or less and resume at 50% dose.
Increases to 75% and full dose should be considered at the start of each vincristine
containing cycle based on patient’s symptoms.

Anticipate autonomic neuropathy resulting in constipation. Laxatives and/or stool
softeners should be used preemptively during vincristine containing cycles. If severe
paralytic ileus occurs vincristine should be stopped until normal bowel movements
are re-established and then resumed at 50% dose. Mild to moderate constipation (< 4
days) is not an indication for interrupting vincristine.

40
Ifosfamide Neurotoxicity
This is an organic brain syndrome that ranges from mild confusion and disorientation
to seizures, ataxia, and coma. It may be aggravated by impaired renal function. It
usually, but does not always, resolve spontaneously, and it may or may not recur
with subsequent doses. If symptoms are mild and transient cycle may continue with
strict avoidance of potentially aggravating co-administered medications such as
sedatives and anticholinergic drugs. Patients who have experienced mild symptoms
( ≤ Grade 2) may receive ifosfamide in subsequent cycles. If neurotoxicity > Grade 2
occurs or symptoms are prolonged, delete ifosfamide from all subsequent cycles and
substitute cyclophosphamide 440 mg/m
2
per day with MESNA uroprotection for 5
days, with 5 days of etoposide. This schedule of fractionated cyclophosphamide has
previously been used in National Wilms Tumor Trial V, Regimen I.

Mucositis

See Appendix B. Chemotherapy doses should not be reduced for mucositis unless all
supportive care remedies outlined in Appendix B have been exhausted.

For Grade 3 or 4 mucositis (mouth or throat pain interfering with ability to hydrate or
aliment adequately, or diarrhea resulting in incontinence and interfering with daily
activities) which persists more than 15 days after a vincristine-doxorubicin-
cyclophosphamide cycle, and is unresponsive to the measures in Appendix B,

41
decrease the doxorubicin dose by 25% in subsequent cycles. Do not decrease the
doses of the other drugs.

For Grade 3 or 4 mucositis which persists more than 15 days after an ifosfamide-
etoposide cycle, reduce both the ifosfamide and etoposide doses by 25% in
subsequent cycles. Re-escalation should be attempted if mucosal toxicity > Grade 2
does not recur.

For Grade 3 or 4 mucositis which persists more than 15 days after a vincristine-
topotecan-cyclophosphamide cycle, reduce the topotecan dose by 25% in subsequent
cycles. Re-escalation should be attempted if mucosal toxicity > Grade 2 does not
recur.

Hematuria or Hemorrhagic Cystitis

Microscopic Hematuria
Transient microscopic hematuria (no more than 2 abnormal urinalyses on two separate
days during a cycle of therapy): no modification of the oxazaphosphorine
(cyclophosphamide or ifosfamide) or MESNA.

Persistent microscopic hematuria (> 2 abnormal urinalyses during a cycle of
therapy):
a) Do not modify the ifosfamide or cyclophosphamide dose.

42
b) Use continuous infusion MESNA, as below.

Gross Hematuria
1. Transient gross hematuria during or following a cycle of therapy (only one
episode, which clears to less than gross hematuria):
a) Do not modify the ifosfamide or cyclophosphamide dose.
b) Use continuous infusion MESNA, as below.

2. Persistent gross hematuria after completion of a cycle of therapy:
a) Hold subsequent ifosfamide or cyclophosphamide until the urine clears to
less than gross hematuria.
b) Reinstitute ifosfamide or cyclophosphamide at full dose, with the
MESNA changed to a continuous infusion.
3. Persistent gross hematuria occurring during a cycle of ifosfamide or
cyclophosphamide:
a) Interrupt the ifosfamide/cyclophosphamide.
b) Withhold further ifosfamide/cyclophosphamide until the next cycle of
therapy or until urine clears.
c) For subsequent cycles give MESNA by continuous infusion.
4. Occurrence of a second episode of gross hematuria or persistence of
microscopic hematuria on the continuous infusion MESNA regimen:

43
a) Continue the ifosfamide or cyclophosphamide when the urine clears to
less than gross hematuria.
b) Double the recommended loading and infusion doses of MESNA.
c) Continue to give MESNA by continuous infusion for 48 hours after the
last dose of ifosfamide/cyclophosphamide.
5. Persistent gross hematuria in the face of this “double dose, continuous
infusion regimen:” discontinue the ifosfamide or cyclophosphamide.
6. All episodes of gross hematuria should be evaluated by cystoscopy. Further
testing, such as urine culture, excretory urogram and voiding cystogram
should also be considered and performed as indicated.

Continuous Infusion MESNA Regimen
The total daily mesna dose is equal to 60% of the daily ifosfamide or
cyclophosphamide dose. Dilute in D5W or NS to a convenient volume (e.g., 120-240
mL/day). The continuous infusion should be started at the same time as the
ifosfamide or cyclophosphamide and finish no sooner than 8 hours after the end of
the ifosfamide or cyclophosphamide infusion.

Hepatotoxicity

Hepatotoxicity is not expected to occur frequently on this study and if observed,
causes should be investigated. However, abnormal liver function may be associated
with increased vincristine and doxorubicin toxicity. Dose adjustments for vincristine,

doxorubicin, etoposide and/or dactinomycin should be made based on the level of
direct bilirubin.

Table 3: Chemotherapy dose modifications for hepatotoxicity.

Hepatotoxicity Vincristine
adjustment
Doxorubicin
adjustment
Etoposide
adjustment
Dactinomycin
adjustment
Grade 1
(Bilirubin <
1.5 X ULN)

Full Dose

Full Dose

Full Dose

Full Dose

Grade 2
Delay 1 week.
Full dose if
resolved to Grade
1 or less.
50% if still Grade
2.
Delay 1 week.
Full dose if resolved
to Grade 1 or less.
50% if still Grade 2.
Delay 1 week.
Full dose if
resolved to Grade
1 or less.
50% if still Grade
2.
Delay 1 week.
Full dose if
resolved to Grade 1
or less.
50% if still Grade
2.
(Bilirubin 1.5-
3 X ULN)
Grade 3, 4
(Bilirubin > 3
X ULN)
Delay 1 week or
until resolved to
Grade 1
Delay 1 week or
until resolved to
Grade 1
Delay 1 week or
until resolved to
Grade 1
Delay 1 week or
until resolved to
Grade 1

Dermatologic Toxicity

Nails
Patients receiving compressed chemotherapy may slough their fingernails. This is
painless and reversible, and no countermeasures are indicated.

Palms and Soles
A few patients may experience painful inflammation and desquamation of the palms
and soles, more often after ifosfamide-etoposide cycles. If this occurs, allow a 21-
day interval in the next cycle, and attempt a 14-day cycle again subsequently.
44

45

Any Other Grade 3 or 4 Toxicities

Delay therapy until toxicity has resolved to Grade 1. Dose reduction of 25% may be
considered at investigator’s discretion. Attempts should be made to re-escalate dose
if toxicity does not recur.

Allergy to Etoposide

Pre-medication (such as diphenhydramine, +/- ranitidine and +/- hydrocortisone) and
slowing of the rate of infusion with etoposide can be tried. Substitution with
etoposide phosphate should be considered if a patient develops a reaction that would
put him/her at risk if further etoposide were given. Etoposide phosphate may be
substituted for Etoposide with pre-medication and administered at the same dose and
rate.

46
CHAPTER 4
EVALUATIONS AND DATA TO BE ACCESSIONED

All baseline studies must be performed prior to starting protocol therapy unless
otherwise noted below.
Table 4: Required and recommended observations during therapy

Required
Observation
Study Entry During
Induction
Prior to Local
Control
During
Continuation
End of
Therapy
History and
Physical Exam
X X
1
X X
1
X
Biopsy X
Electrolytes,
creatinine,
phopsphorus,
calcium,
bilirubin, AST,
ALT
X X
1
X
1

LDH X
Recommended

Urinalysis X X
1
X X
1

Pregnancy Test
2
X
Bilateral Bone
Marrow Biopsy
and Aspirate
X
Whole Body
MDP Bone
Scintigraphy
X X X X
FDG-PET X
3
X X X
Radiograph of
primary site
(frontal and
lateral views)
4
X X X
MRI with
gadolinium
(primary site)
5
X X X X

CT Scan of
Chest
6
X X X
Radiograph of
chest (frontal and
lateral views)
X
Recommended

CBC, Plt, Diff. X X
7
X X
ECHO or MUGA X X
8
X
Orthopedic
functional
assessment
9
X
Recommended

1 Obtain prior to each cycle.
2 Pregnancy test required prior to study enrollment for females of childbearing potential only.

47
3 Is strongly recommended if the primary bone tumor does not have uptake on bone scintigraphy.
4 Obtain if bone lesion.
5 Note that MR may not be interpretable if the patient has undergone resection of the primary bony
site of disease with placement of a massive metallic prosthesis. Imaging of the primary site may
be limited to plain radiographs (and bone scintigraphy).
6 CT Scan of the chest should use spiral technique (if available) with a single breathhold, for
patients able to cooperate.
7 Obtain on Day 1 and 8 of each cycle. Obtain blood counts every Monday, Wednesday and Friday
(or 3 other non-consecutive days per week) after Day 14 until the criteria for starting the next
cycle are satisfied.
8 Electrocardiogram and echocardiogram with determination of shortening fraction or MUGA
(radionuclide angiogram) for ejection fraction is to be obtained prior to every other doxorubicin
cycle until a dose of 300 mg/m
2
is reached. Once that endpoint is met, patients must then have
echocardiograms prior to every doxorubicin cycle. Use the same test each time for consistency in
evaluation.
9 Regular assessment should include range of motion, limb length assessment, gait and pain
assessment.

Follow-up

If a relapse is suspected, a biopsy confirmation of the suspected recurrence is
recommended in most cases. In case of local relapse, metastatic work-up is
recommended for confirmation of extent of recurrence.

General follow-up should occur as per local institutional standards and as appropriate
for individual patient care and known long-term toxicities of agents received.
Refer to COG Late Effects Guidelines for recommended post treatment follow-up at:
http://www.childrensoncologygroup.org/disc/LE/default.htm

48
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY
AND OFF STUDY CRITERIA

Criteria for Removal From Protocol Therapy
a) Progressive disease.
b) Disease detected at new sites.
c) Biopsy positive residual disease after all local control measures completed.
d) Refusal of further protocol therapy by patient/parent/guardian.
e) Completion of planned therapy.
f) Physician determines it is in patient’s best interest.
g) Development of a second malignancy.
Patients who are off protocol therapy are to be followed until they meet the criteria for
Off Study (see below). Follow-up data will be required unless consent was withdrawn.

Off Study Criteria
a) Death.
b) Lost to follow-up.
c) Entry into another COG therapeutic study.
d) Withdrawal of consent for any further data submission.
e) The tenth anniversary of the study's closure to accrual.

49
CHAPTER 5
STATISTICAL CONSIDERATIONS

Statistical Design

This is a pilot study to assess the feasibility of administering treatment in the doses
and schedule described above. Patients will be enrolled as a single cohort and
assigned to receive therapy as described in Sections 4 and 5 of the protocol.

We will consider three components of feasibility:
(1) incidence of death from complications of therapy while the patient is on protocol
therapy or within one month of terminating protocol therapy;
(2) the incidence rate of dose-limiting toxicity while on protocol therapy; and
(3) the time from the start of therapy to the initiation of local control measures
planned for Week 13 of therapy.

Patient Accrual and Expected Duration of Trial

A maximum of 30 patients evaluable for the interval between start of therapy to the
initiation of local control measures will be required to address the goals of the study.
We estimate this will require approximately 35 patients to be enrolled given
historical rates of early death and refusal of protocol therapy prior to local control.
The accrual rate observed with AEWS0031 was approximately 11 patients per

50
month. Enrollment to the proposed study should be completed within six months of
the opening of the study considering historically study accrual is slower than
projected in the first few months after a study is opened.

Methods of Analysis

Incidence of death from complications of therapy while the patient is on protocol
therapy or within one month of terminating protocol therapy:
Any patient who receives at least one cycle of protocol therapy, or who dies as a
result of complications of therapy prior to completing one cycle of therapy will be
evaluable for this outcome. Any patient who dies while receiving therapy, or within
one month of stopping protocol therapy, and whose death is considered by the
institutional investigator to be possibly, probably or likely related to treatment will
be considered an “on treatment death.” In all other cases where the patient is
evaluable for this endpoint, the patient will not be considered an “on treatment
death.” If, at any time 2 or more patients are considered “on treatment deaths,” the
study will be suspended and considered for early termination or modification. If the
true “on treatment death” probability is 1% (a value considered consistent with the
results of INT-0091), the regimen will be considered acceptable with respect for risk
of “on treatment death” with probability 0.96. If the true “on treatment death”
probability is 10%, the regimen will be considered unacceptable with respect for risk
of “on treatment death” with probability 0.82.

51
The incidence rate of dose-limiting toxicity while on protocol therapy:
Since there has been no previous experience with interval compression using
vincristine, topotecan and cyclophosphamide, the investigators would like to ensure
that the regimen is safe. In order to monitor the safety of this regimen, all patients
will be evaluated for serious complications during the administration of treatment
(“dose-limiting toxicities;” DLTs). Any patient who receives at least one cycle of
protocol therapy, or who is removed from protocol therapy partly or solely because
of a dose-limiting toxicity (see below) will be evaluable for this outcome. A dose
limiting toxicity is: (1) a Grade 3 or greater non-hematological adverse event that is
possibly, probably or likely related to therapy with the specific exception of Grade 3
or greater nausea or vomiting controlled by standard supportive care measures,
Grade 3 infection and Grade 3 alopecia; or (2) Grade 4 or higher hematological AE
that delays the administration of therapy at least two weeks. Patient follow-up on
protocol therapy will vary as a result of issues such as time to recurrence and also
because of compliance with therapy. Each patient, therefore, will be evaluated for
toxicity at the end of each of four potential reporting periods: (1) week 12 (2) week
22 (3) week 28 and (4) week 37. The per-reporting period incidence of all dose-
limiting toxicities by toxicity type will be tabulated for each reporting period. If
more than 20% of patients experience DLT during any particular reporting period the
study will be identified for possible modification. For example, if a reporting period
has 30 patients evaluated for DLT, if 6 or more have DLT, the therapy will be
considered for modification. If the reporting period is associated with a true

52
incidence of DLT of 30%, the therapy will be identified as excessively toxic with
probability 0.92. If the reporting period is associated with a true incidence of DLT of
12%, the therapy will be identified as tolerable with probability 0.86. For example,
prolonged delays because of neutropenia are considered DLT, even if such delays do
not eventually result in delay in the timing of local control. If the true underlying rate
of DLT were 30%, the rule developed would identify the therapy as intolerable with
probability of 92%. The statistical characteristics for reporting periods with fewer
patients evaluated are similar, although the sensitivity and specificity are reduced.

The time from the start of therapy to the initiation of local control measures planned
for Week 13 of therapy:
Any patient who completes the first reporting period and is evaluated for local
control will be evaluated for this outcome measure. The average number of weeks
from enrollment to the end of the last week of chemotherapy prior to local control
will be the sample characteristic used to evaluate the feasibility of the accelerated
regimen. This average will be compared with 12 weeks using a one-sided test of size
0.05. The probability with which this accelerated regimen will be identified as not
providing sufficient compression as a function of the true time to complete induction
is given in the table below.

53
Table 5: Probability table of identifying accelerated strategy as not feasible.

True Average
Number of Weeks to
Complete Pre-Local
Control Therapy
True Standard
Deviation of Number
of Weeks to Complete
Pre-Local Control
Therapy
Probability of
Identifying the
Accelerated
Strategy as Not
Feasible
12.5 2 0.38
12.5 1.5 0.55
13 2 0.85
13 1.5 0.97
13.5 2 0.99
13.5 1.5 > 0.99
14 2 > 0.99
14 1.5 > 0.99

Patients will be followed until the completion of all protocol therapy. The length of
time in weeks required to complete post local control therapy will be characterized
by the average and standard deviation of the number of weeks, segregated by type of
local control (did contain radiation therapy vs. did not contain radiation therapy).
The statistical rule will identify the treatment as resulting in insufficient interval
compression if, on the average, patients require 13 rather than 12 weeks to complete
pre-local-control chemotherapy.

Evaluation of Sustained Compression
In a preliminary analysis of AEWS0031, a mixed effects model relating course
length (dependent variable) to course number and randomized treatment assignment
(independent variables) yielded a fitted slope parameter of 0.3 days per course with a
standard error of 0.11 and an effect associated with randomization to the compressed

54
regimen of -7.8 days. We will conduct the same analysis once all patients have
completed treatment. The fitted “slope” of course length as it relates to course
number will be compared with the above historical result, viz., estimated mean of 0.3
days per course with a standard error of 0.11 days. This analysis will only be done if
the regimen is considered tolerable and there is sufficient dose compression up to the
time of local control. If this test is significant at the 0.05 level or less (one-sided), the
therapy will be identified for possible modification since there does not appear to
sufficient sustained dose compression compared with AEWS0031.

Estimation of Event-free Survival (EFS)
EFS will be defined to be the time from enrollment on the study until disease
progression, occurrence of a second malignant neoplasm, death or last contact,
whichever comes first. Disease progression, occurrence of a second malignant
neoplasm or death will be considered an analytic event; in all other cases, the patient
will be considered censored at last contact. Survival (S) will be defined to be the
time from enrollment on the study until death or last contact, whichever comes first.
Death will be considered an analytic event; in all other cases, the patient will be
considered censored at last contact. EFS and S will be characterized by the method
of Kaplan and Meier.
22
No formal statistical testing will be done for these two
outcome measures.

55

CHAPTER 6
EVALUATION CRITERIA

Common Terminology Criteria for Adverse Events v3.0 (CTCAE)

This study will utilize the CTCAE of the National Cancer Institute (NCI) for toxicity and
performance reporting. A copy of the current version of the CTCAE can be downloaded
from the CTEP home page (http://ctep.cancer.gov/). Additionally, toxicities are to be
reported on the appropriate data collection forms.

Response Criteria for Patients with Solid Tumors

This study will use three-dimensional measurements of the primary tumor rather than single
dimension as used in RECIST. Regional nodal disease if present will be evaluated by single
dimension measurement. The value of 3D volume measurement has already been
substantiated in several studies.
23-25
In addition, bone tumors, which will constitute the
majority of tumors on this trial, are considered non-measurable according to RECIST
guidelines. The evaluation of response in multiple lesions as outlined in RECIST will not
apply, as this study is limited to patients with localized disease only.

Response of the Primary Tumor
Based on previously published data correlating tridimensional measurements to bi-
directional and unidirectional measurements the following response criteria for the primary
tumor will be used:
25

56
Complete Response (CR): Complete disappearance of the tumor confirmed at ≥ 4
weeks.

Partial Response (PR): At least 64% decrease in tumor volume compared to the
baseline.

Progressive Disease (PD): At least 40% increase in tumor volume compared to the
smallest measurement obtained since the beginning of
therapy.

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD taking as reference the smallest
disease measurement since the treatment started.

Response of Pathologic Lymph Nodes
The response of lymph nodes will be based on the report of an international workshop to
standardize response criteria for non-Hodgkin lymphomas.
23

Complete Response:
1) All nodes measure < 1.0 cm OR
2) All lymph nodes with 1.5 cm maximal transverse diameter must decrease to less
than 1.5 cm, and all nodes 1.1-1.5 cm in maximal transverse diameter before
treatment must decrease to 1.0 cm or less OR

57
3) More than 75% decrease in the sum of the products of the two dimensions for
each node (SPD)

Partial Response: At least 50% decrease in SPD.

Progressive Disease: At least 50% increase from nadir in the SPD.

Stable Disease: Neither sufficient shrinkage to qualify for PR nor sufficient
increase to qualify for PD taking as a reference the smallest
disease measurement since the treatment started.
Overall Response Assessment
The overall response assessment takes into account response in the primary tumor,
associated pathologic lymph nodes, and the appearance of new lesions, where applicable,
according to the criteria described in the table below. The overall response assessment is
shown in the last column, and depends on the assessments of the primary tumor, adenopathy
and new lesions in the preceding columns.

Table 6: Response assessment criteria.
Primary
tumor
Lymph nodes New Lesions Overall Response
CR CR No CR
CR PR/SD No PR
PR PR/SD No PR
SD Non-PD No SD
PD Any Any* PD
Any PD Any* PD
Any Any Yes* PD

*Solitary, small (< 1 cm) and osseous sites of suspected new disease should be
biopsied.

58

IMAGING STUDIES REQUIRED AND GUIDELINES FOR OBTAINING

Table 7: Required and Recommended Imaging (All imaging studies are required unless
otherwise noted).

Table 7a: At Presentation and Prior to Local Control

Site Anatomic Imaging Functional
Imaging
Timing
Primary Frontal and lateral
radiographs
Required at presentation
and prior to local control
Primary MRI with
gadolinium

- Required at presentation
and prior to local control
- The pre-surgery exam
should be performed within
4 weeks of local control
Chest CT Required at presentation
and prior to local control
Chest Frontal and lateral
radiographs
Recommended at
presentation only
Whole
body
MDP bone
scintigraphy
Required at presentation
and prior to local control
Whole
body
FDG-PET - Strongly recommended at
presentation if the primary
bone tumor does not have
uptake on bone
scintigraphy.
- Recommended prior to
local control, particularly if
primary bone tumor
positive on prior PET and
negative on bone
scintigraphy.

59

Table 7b: After Local Control

Site Anatomic Imaging Functional
Imaging
Timing
Primary Frontal and lateral
radiographs
Within 2 weeks
of surgery
Primary MRI with gadolinium or
CT scan with IV contrast
(in patients without
significant metallic artifact
at primary tumor site).
3 to 4 months
after local control

Table 7c: Surveillance on Chemotherapy and End of Therapy Evaluations

Site Anatomic
Imaging
Functional
Imaging
Timing
Primary Frontal and
lateral
radiographs
Required – After 10 cycles
Chest CT Required – After 10 cycles
Whole
body
MDP bone
scintigraphy
Required –At end of cytotoxic
chemotherapy (unless bone
scintigraphy negative and FDG-PET
positive at presentation)
- Sooner if symptoms or abnormal
imaging (and surgical or other
intervention contemplated AND
primary tumor positive on prior bone
scintigraphy)
Whole
body
FDG-PET Required – At end of cytotoxic
chemotherapy if bone scintigraphy
negative and FDG-PET positive on
prior imaging
Recommended - At end of cytotoxic
chemotherapy (unless bone
scintigraphy positive and FDG-PET
negative at presentation)
- Sooner if symptoms or abnormal
imaging (and surgical or other
intervention contemplated AND
positive on prior FDG-PET)
Primary MRI with
gadolinium
or CT scan
with IV
contrast
Recommended if symptoms or
abnormal imaging (and surgical
intervention or radiation therapy
contemplated)

60

Table 7d: Recommended Surveillance Post-Chemotherapy

Site Anatomic Imaging Functional
Imaging
Timing
Primary Frontal and lateral
radiographs
q 3 months x 8,
then
q 6 months x 6,
then
q 12 months x 5
Chest Frontal and lateral
radiographs
q 3 months x 8,
then
q 6 months x 6,
then
q 12 months x 5
Chest CT If abnormal chest
radiographs
Primary MRI with gadolinium or
CT scan with IV contrast
If symptoms or
abnormal imaging
(and surgical or
other intervention
contemplated)
Whole
body
MDP bone
scintigraphy

If symptoms or
abnormal imaging
(and primary tumor
positive on prior
bone scintigraphy
AND surgical or
other intervention
`contemplated)
Whole
body
FDG-PET

If symptoms or
abnormal imaging
(and primary tumor
positive on prior
FDG-PET AND
surgical or other
intervention
contemplated)

61

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adjuvant chemotherapy for women with high-risk node-positive breast cancer: A
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4. Hunold A, Weddeling N, Paulussen M, et al: Topotecan and cyclophosphamide in
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2. Saylors RL III, Stine KC, Sullivan J, et al: Cyclophosphamide plus topotecan in
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19. Venturini M, Del Mastro L, Testore F, et al: Erythropoietin and granulocyte-
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21. Womer RB, Daller RT, Fenton JG, et al: Granulocyte colony stimulating factor
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64

APPENDIX A

SAMPLE RESEARCH INFORMED CONSENT

A Pilot Study of Chemotherapy Intensification by Adding Vincristine,
Topotecan and Cyclophosphamide to Standard Chemotherapy Agents
with an Interval Compression Schedule in Newly Diagnosed Patients
with Localized Ewing Sarcoma Family of Tumors

When we say “you” in this consent form, we mean you or your child; “we” means the
doctors and other staff.

WHY ARE YOU BEING INVITED TO TAKE PART IN THIS STUDY?

This study is called a clinical trial. A clinical trial is a research study involving treatment of a
disease in human patients. This study is organized by the Children’s Oncology Group
(COG). COG is an international research group that conducts clinical trials for children with
cancer. More than 240 hospitals in North America, Australia, New Zealand, and Europe are
members of COG.

You are being asked to take part in this research study because you have been diagnosed
with a tumor that belongs to the Ewing sarcoma family of tumors.

Ewing sarcoma is a type of cancer that forms a tumor in the bone or soft connective tissues
around the bones. You are being asked to take part in this study because your tumor is
localized. A localized tumor is one that has not spread to any other places in the body.

It is common to enroll children and adolescents with cancer in a clinical trial that seeks to
improve cancer treatment over time. Clinical trials include only people who choose to take
part. You have a choice between a standard treatment for Ewing sarcoma and this clinical
trial.

Please take your time to make your decision. Discuss it with your friends and family. We
encourage you to include your child in the discussion and decision to the extent that she or
he is able to understand and take part.

WHAT IS THE CURRENT STANDARD OF TREATMENT FOR THIS DISEASE?

The current standard treatment for localized Ewing sarcoma is to give people chemotherapy,
(cancer fighting medicine) and then either remove the tumor by surgery or treat the tumor
with radiation therapy. Some people will have both surgery and radiation therapy. The
standard chemotherapy drug combinations used to treat Ewing sarcoma are vincristine,
doxorubicin and cyclophosphamide (VDC), and ifosfamide and etoposide (IE). These
combinations are given in alternating 3-week intervals that are repeated many times.

65
Previous clinical trials have shown these drugs to be effective against localized Ewing
sarcoma.

WHY IS THIS STUDY BEING DONE?

In this study, researchers want to find out if we can improve the treatment for your disease
by adding a drug called topotecan to the 5 drugs used in standard treatment. We chose the
drug topotecan because the combination of topotecan and cyclophosphamide has been found
to be useful in treating some patients with Ewing sarcoma that has spread to other parts of
the body (metastatic disease) or has come back after treatment (relapsed). The combination
of vincristine-topotecan-cyclophosphamide has been used safely in children and adolescents
with other types of sarcoma. It is not known if adding topotecan will be helpful for localized
disease, and it may increase the side effects of treatment.

Researchers also want to strengthen your treatment by giving the drugs over a shorter period
of time. This is sometimes called compressed therapy. Compressed therapy using VDC and
IE (but not topotecan) has been used safely in children and adolescents with Ewing Sarcoma.
Early clinical trial results have shown that Ewing Sarcoma patients treated with compressed
therapy have better survival rates than those treated with standard length therapy.
Compressed therapy has also been used safely in people with other types of cancer. Getting
compressed therapy with topotecan may improve your chances of getting rid of the cancer
for as long as possible, and it may increase the side effects of treatment.

In summary, the experimental chemotherapy on this study is different from the standard
chemotherapy in 2 ways:
1) The drug combination of vincristine-topotecan-cyclophosphamide is added to the
standard chemotherapy combinations; this means you will get 1 drug more than is standard.
2) The chemotherapy will be given in cycles that last 2 weeks rather than the standard 3
weeks; this means that the total treatment time will be shorter (compressed).

The overall goal of this study is to find out the effects, good and/or bad, of adding the drug
topotecan to the standard 5-drug chemotherapy for Ewing sarcoma, when therapy is given on
a compressed schedule.

HOW MANY PEOPLE WILL TAKE PART IN THE STUDY?

The total number of people enrolled on this study is expected to be 35.

WHAT WILL HAPPEN ON THIS STUDY THAT IS RESEARCH?

In standard therapy the drugs are given in 3 combinations: vincristine-doxorubicin-
cyclophosphamide (VDC) followed by ifosfamide-etoposide (IE) and vincristine-
cyclophosphamide (VC). Each combination is given over 21 days and each 21 day period is
called a cycle.

Subjects on this study will have topotecan added to the 5 standard chemotherapy drugs used
to treat Ewing sarcoma. The drug combinations given on this study are: vincristine-

66
topotecan-cyclophosphamide (VTC) followed by vincristine-doxorubicin-cyclophosphamide
(VDC) and ifosfamide-etoposide (IE).

In addition, each cycle of chemotherapy on this study will last 14 days instead of the
standard 21 days. As a result, the treatment on this study will last about 9 months. This is
shorter than standard therapy which usually lasts about 12 months.

The addition of topotecan and the shorter schedule means that the total dose of some drugs
given on this study will be different to the total dose given on standard therapy. The
differences include:
• The total dose of vincristine given on this study will be more than is given in
standard therapy.
• The total dose of cyclophosphamide will be more than is given in standard therapy.
• The study therapy has one less IE cycle than standard therapy.

Treatment Plan
The treatment plan involves chemotherapy along with surgery and/or radiation therapy. The
treatment is divided into 3 stages: Induction, Local control and Continuation therapy.

- Induction therapy is the use of chemotherapy to reduce/get rid of the cancer. The goal is to
kill cancer cells and shrink the tumor so that the surgery/radiation therapy will be easier
and safer. We also want to stop the disease from spreading.
- Local control is treatment directly to the tumor, and will be surgery and/or radiation
therapy.
- Continuation therapy is treatment intended to kill any remaining cancer cells so that the
tumor won’t come back.

Induction will be 6 cycles of chemotherapy, and last around 12 weeks. Local Control will
usually begin at about Week 13 and may be surgery, radiation therapy, or both (as described
below). That decision will be made by your doctors and will depend on the location and size
of your tumor. Continuation will consist of 11 cycles (22 weeks) of chemotherapy and may
be started during the period of Local Control. This means that sometimes radiation therapy
and chemotherapy will be given in the same weeks.

Local Control
• If you are to have surgery only, this will happen after you recover from induction
therapy (likely during Week 13).
• If you are to have radiation therapy only, it will likely be given during Weeks 13-19.
• If you are to have surgery first followed by radiation therapy, surgery will occur
after you recover from induction therapy (likely during Week 13). Radiation therapy
will then begin after you recover from surgery (likely at Week 15).
• If you are to have radiation therapy first followed by surgery, radiation therapy will
be given during Weeks 13-19 and surgery will happen after you recover from Cycle
11 of chemotherapy (likely during Week 25).

The exact timing of chemotherapy and local control will depend on how well you recover
from the drugs given during each cycle. You will also need time to heal from any surgery
done, and from the effects of radiation therapy.

While on this study, a number of tests and procedures will be done so that we can see how
you are responding to therapy. These tests would also be done as part of standard therapy for
Ewing sarcoma and are listed in Attachment #1.

Treatment Plan Tables
Most drugs on this study will be given using a needle or tubing inserted into a vein (IV).
Drugs can be given by IV push over several minutes, or by infusion over minutes or hours.

The drug topotecan will be given along with the standard drugs vincristine and
cyclophosphamide. The table below describes how drugs will be given during each 14-day
cycle of VTC.

Drug How the drug will be given Days of each VTC cycle
Vincristine (V) IV push 1 and 8
Topotecan (T) IV over 30 minutes 1-5
Cyclophosphamide (C) IV over 1 hour 1-5

The way that the 5 standard chemotherapy drugs will be given during the 14-day cycles on
this study is described below. The standard drugs will be given in 2 combinations:
vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE).

Drug How the drug will be given Days
Vincristine (V) IV push Days 1 and 8 of each VDC
cycle
Doxorubicin (D) IV over 15 minutes Days 1 and 2 of each VDC
cycle
Cyclophosphamide (C) IV over 1 hour Day 1 of each VDC cycle

Ifosfamide (I) IV over 1 hour Days 1-5 of each IE cycle
Etoposide (E) IV over 1 hour Days 1-5 of each IE cycle

67

VTC: vincristine-topotecan-cyclophosphamide
IE: ifosfamide-etoposide
VDC: vincristine-doxorubicin-cyclophosphamide
XRT: radiation therapy

68

The table below shows the order in which the chemotherapy combinations will be given on this
study.

Experimental Therapy (Each cycle is 14 days)
Cycle Drugs
1 VTC
2 IE
3 VDC
4 IE
5 VTC
6 VDC
Local control with surgery and/or radiation therapy will begin around Week 13.
Chemotherapy will continue at around Week 15.
7 VTC
8 IE
9 IE
10 VTC
11 VDC
12 IE
13 VDC
14 VTC
15 IE
16 VDC
17 IE
This is the end of therapy, at about Week 36.

You will also be given other drugs known as supportive care drugs. They will be given to help
reduce the side effects of the chemotherapy drugs.
- Filgrastim (G-CSF) will be given to help your white blood cells recover as quickly as
possible after chemotherapy. It will be given through a needle inserted just below the
surface of the skin 24 hours after the last dose of chemotherapy in each cycle. It will be
given once or twice a day until your blood counts recover enough to start the next cycle of
chemotherapy.
- Mesna will be given to protect your bladder. It will be given IV or by mouth before, during
and after the cyclophosphamide and ifosfamide doses.
- Dexrazoxane will be given to help protect your heart from damage that might be caused by
doxorubicin. It will be given IV before doxorubicin in the fourth and fifth cycles of VDC.

Some copies of the radiology (x-ray) films used to make the diagnosis of your disease will
be sent to a central review center as part of COG quality control. The central review of films
is done to make sure that every COG institution performs at an acceptable standard. You will
not get any information from these reviews.

69

HOW LONG IS THE STUDY?

Subjects in this clinical trial are expected to receive treatment on this study for about 9
months. After treatment, subjects will have follow-up examinations and medical tests. We
will continue to collect some medical information about how you are doing for 10 years after
the last subject starts the study.

Your doctor or the study doctor may decide to take you off this study under the following
circumstances:
• if he/she believes that it is in your best interest
• if your disease comes back during treatment
• if you experience side effects from the treatment that are considered too severe
• if new information becomes available that shows that another treatment would be better
for you

You can stop participating at any time. However, if you decide to stop participating in the
study, we encourage you to talk to the study doctor and your regular doctor first. They will
help you to stop safely.

WHAT ARE THE RISKS OF THE STUDY AND HOW ARE THE RISKS
DIFFERENT FROM TREATMENT?

Treatment Risks
All people who receive cancer treatment are at risk of having side effects. In addition to
killing tumor cells, cancer chemotherapy can damage normal tissue and produce side effects.
Side effects are usually reversible when the medication is stopped but occasionally persist
and cause serious complications. A person can die from these and other complications.

Common side effects include nausea, vomiting, hair loss, and fatigue. Drugs may be given to
prevent or decrease nausea and vomiting. Hair loss is usually temporary but on very rare
occasions it may be permanent. Some chemotherapy may lead to sterility. Sterility is the
inability to have children. There is also the possibility that a second cancer may develop
years later as a result of the chemotherapy. The risks of the individual drugs given as
standard treatment and risks of radiation therapy are listed in the tables in Attachment #2.
Side effects can be increased when chemotherapy drugs are combined.

The most common serious side effect from cancer treatment is a lowering of the number of
blood cells resulting in anemia, increased chance of infection, and bleeding tendency. Low
blood counts are described in the COG Family Handbook for Children with Cancer. You
will be taught more about caring for your child when his or her blood counts are low.

There is a risk that the treatment plan will not cure the cancer or that the cancer can go away
after the treatment and then come back at a later date.

For Women:
The treatment on this study can affect an unborn child. You should not become pregnant or
breast feed your baby while being treated on this study. If you are sexually active and are at
risk of getting pregnant, you and your male partner(s) must use an effective method to avoid

70
pregnancy or you must not have sex. The study doctor will talk to you about acceptable
methods to avoid pregnancy while you are being treated on this study. You will have to use
the chosen method to avoid pregnancy or abstain (not have sexual intercourse) the whole
time you are being treated on this study. You may need to continue this for a while, even
after you finish the cancer treatment, so talk to your doctor about the length of time you need
to avoid pregnancy or abstain. Natural family planning and the rhythm method will not be
permissible means of avoiding pregnancy during study participation. If you have questions
about this or want to change your method to avoid pregnancy during therapy, please ask
your doctor. If you become pregnant during the research study, please tell the investigator
and your doctor immediately.

If you are nursing a baby, the drugs used in this research could pass into the breast milk. You
should not nurse your baby for the whole time you are getting the study medicines. You may
need to continue this for a while, even after you finish the cancer treatment, so talk to your
doctor about the length of time you need to avoid nursing.

For Men:
The treatment on this study can damage sperm. You should not father a child while on this
study as the treatment may indirectly affect an unborn child. If you are sexually active and
are at risk of causing a pregnancy, you and your female partner(s) must use a method to
avoid pregnancy that works well or you must not have sex. The investigator will talk to you
about the acceptable methods to avoid pregnancy while you are being treated on this study.
You will have to use the chosen method to avoid pregnancy or abstain (not have sexual
intercourse) the whole time you are being treated on this study. You may need to continue
this for a while, even after you finish the cancer treatment, so talk to your doctor about the
length of time you need to avoid pregnancy or abstain. Natural family planning and the
rhythm method will not be permissible means of avoiding pregnancy during study
participation. If you have questions about this or want to change your method to avoid
pregnancy during therapy, please ask your doctor. If your partner becomes pregnant during
the research study, please tell the investigator and your doctor immediately.

Risks of Study
The chemotherapy treatment that is being studied could be less effective than the current
standard treatment. The addition of topotecan and the compressed schedule mean that the
total dose of some of the standard drugs, which are known to be effective, will be reduced.

There is a possibility that the side effects of the standard drugs may be worse than normal
because the total dose of some other drugs will be greater than is standard.

The compressed schedule may also increase side effects. For example, some patients treated
with standard therapy on a compressed schedule had painful peeling of the skin on their
palms and soles. This healed without problems, but caused chemotherapy to be given at
intervals longer than 14 days afterwards.

The addition of topotecan to the standard drugs may cause unknown or increased side effects
compared to the standard therapy.

71

Risks and side effects related to topotecan include:

Likely Less Likely Rare but serious
Diarrhea

Nausea

Vomiting

Constipation

Fewer white blood cells,
red blood cells and
platelets in the blood.

A low number of white
blood cells can make it
easier to get infections

A low number of red
blood cells can make you
feel tired and weak

A low number of platelets
causes you to bruise and
bleed more easily

Fever including fever
with a low white blood
cell count which could
indicate infection and
may require
hospitalization and
treatment with antibiotics

Pain which may be in
your abdomen, back or
bones

A feeling of weakness
and/or tiredness

Temporary hair loss

Loss of appetite

Elevation in the blood of
certain enzymes or
bilirubin found in the liver
which could indicate liver
irritation or damage

Headache

Rash, hives, itching or a
red bumpy rash

A mild lowering of the
blood pressure which
usually does not require
treatment

Inflammation and/or sores
in the mouth, throat
and/or esophagus

An infection in the blood
which will require
admission to the hospital
and treatment with
antibiotics

Numbness and tingling in
the fingers and toes

Small amount of blood
and/or protein in the urine
or an elevation in blood
creatinine which may
indicate mild kidney
damage

Shortness of breath

Muscle or joint aches and
pains

Chest pain

Shaking chills

Severe allergic reaction
which can be life
threatening with shortness
of breath, low blood
pressure and a rapid heart
rate

Severe allergic reaction
which can be life
threatening with rapid
build-up of fluid under the
skin, in the lining of the
intestine and possibly in the
throat or swelling of the
tongue which could make it
difficult to breathe

Bleeding into the tumor
which may cause damage
depending on the location
of the tumor

72

In addition to the risks described above, there may be unknown risks, or risks that we did not
anticipate, associated with being in this study.

ARE THERE BENEFITS TO TAKING PART IN THE STUDY?

We hope that you will get personal medical benefit from participation in this clinical trial,
but we cannot be certain.

The potential benefits could include a better chance that we can get rid of the cancer for as
long as possible (maybe for the rest of your life), and a shorter time to be treated
successfully.

We expect that the information learned from this study will benefit other patients in the
future.

WHAT OTHER OPTIONS ARE THERE?

Instead of being in this study, you have these options:

• Current standard therapy. Standard therapy is described on page 1. Your doctor will
discuss it with you in more detail.
• Taking part in another study

Please talk to your doctor about these and other options.

WHAT ABOUT CONFIDENTIALITY?

Efforts will be made to keep your personal information confidential. We cannot guarantee
absolute confidentiality. Your personal information may be disclosed if required by law.

The Children’s Oncology Group has received a Certificate of Confidentiality from the
federal government, which will help us protect the privacy of our research subjects.
Information about the certificate is included in Attachment #3.

Organizations that may inspect and/or copy your research records for quality assurance and
data analysis include groups such as:

• Children's Oncology Group
• Representatives of the National Cancer Institute (NCI), Food and Drug Administration
(FDA), and other U.S. and international governmental regulatory agencies involved in
keeping research safe for people
• The Institutional Review Board of this hospital
• Pediatric Central Institutional Review Board (CIRB) of the National Cancer Institute

73

WHAT ARE THE COSTS?

Taking part in this study may lead to added costs to you or your insurance company. Please
ask about any expected added costs or insurance problems. Staff will be able to assist you
with this.

In the case of injury or illness resulting from this study, emergency medical treatment is
available but will be provided at the usual charge. No funds have been set aside to
compensate you in the event of injury. However by signing this form, you are not giving up
any legal rights to seek to obtain compensation for injury.

You or your insurance company will be charged for continuing medical care and/or
hospitalization.

For more information on clinical trials and insurance coverage, you can visit the National
Cancer Institute’s Web site at http://cancer.gov/clinicaltrials/understanding/insurance-
coverage. You can print a copy of the “Clinical Trials and Insurance Coverage” information
from this Web site.

If you choose to enroll on this study, this institution will receive some money from the
Children’s Oncology Group to perform the research.

WHAT ARE MY RIGHTS AS A PARTICIPANT?

Taking part in this study is voluntary. You may choose not to be in this study. If you decide
not to be in this study, you will not be penalized and you will not lose any benefits to which
you are entitled. You will still receive medical care.

You may stop being in the study at any time. If you stop being in the study, you will not be
penalized and you will not lose any benefits to which you are entitled. Physicians and
hospital personnel will still take care of you.

We will tell you about new information that may affect your health, welfare, or willingness
to stay in this study. A committee outside of COG closely monitors study reports and
notifies institutions if changes must be made to the study. Members of COG meet twice a
year to evaluate results of treatment and to plan new treatments.

During your follow-up visits after treatment, you may ask to be given a summary of the
study results after they are written up. This may be several years after treatment for all
people on the study is completed.

74

WHOM DO I CALL IF I HAVE QUESTIONS OR PROBLEMS?

For questions about the study or if you have a research-related problem or you are injured,
contact Dr. XXXX or your doctor at XXXXX.

If you have any questions about your rights as a research participant or any problems that
you feel you cannot discuss with the investigators, you may call XXXX IRB Administrator
at XXXX.

If you have any questions or concerns that you feel you would like to discuss with someone
who is not on the research team, you may also call the Patient Advocate at XXXX.

75
WHERE CAN I GET MORE INFORMATION?

The COG Family Handbook for Children with Cancer has information about specific
cancers, tests, treatment side effects and their management, adjusting to cancer, and
resources. Your doctor can get you this Handbook, or you can get it at www.curesearch.org/

Visit the NCI's Web site at http://www.nci.nih.gov/cancerinfo/

If you are in the United States, you may call the NCI's Cancer Information Service at:
1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615

Information about long-term follow-up after cancer treatment can be found at:
http://www.survivorshipguidelines.org/

You will get a copy of this form. You may also ask for a copy of the protocol (full study
plan).

SIGNATURE
I have been given a copy of all _____ [insert total number of pages] pages of this form.
The form includes three (3) attachments.

I agree to take part in this study.

Participant______________________________________ Date_____________

Parent/Guardian_________________________________ Date_____________

Parent/Guardian_________________________________ Date_____________

Physician/PNP obtaining consent____________________ Date_____________

IRB# IRB Approved:

76
Attachment #1

Tests and Procedures Common to Patients Given Standard
Therapy for Ewing Sarcoma

Methods for Giving Drugs
Various methods will be used to give drugs to patients. Some drugs will be given by tablet or
liquid swallowed through the mouth (PO). Other drugs are given by inserting a needle into
the tissue just under the skin. This method is called a subcutaneous (SQ) injection. Most
drugs on this study will be given using a needle or tubing inserted into a vein (IV).

Central Line
For drugs to be given by vein, your doctor will likely recommend that you have a central
venous line placed. A description of the types of central lines is in the COG Family
Handbook for Children with Cancer.

Standard Tests and Procedures
The following tests and procedures are part of regular cancer care and may be done even if
you do not join the study.
• Frequent labs to monitor blood counts and blood chemistries.
• Urine tests to measure how the kidneys and bladder are functioning.
• Pregnancy test for females of childbearing age before treatment begins.
• X-rays and scans to monitor the response to treatment.
• Tests to monitor heart function.
• Bone marrow aspirations and biopsies before starting therapy. The bone marrow
procedure is described in the COG Family Handbook for Children with Cancer.

Whether you join this study or have standard therapy, you will likely have surgery and/or
radiation therapy. The procedures and risks of surgery and radiation therapy will be
discussed with you when you sign the separate consents for these therapies.

77
Attachment #2

Risks of Standard Drugs and Radiation Used to Treat Ewing Sarcoma

Risks and side effects related to cyclophosphamide include those which are:

Likely Less Likely Rare but serious
Loss of appetite

Nausea

Vomiting

Fewer white blood cells,
red blood cells and
platelets in the blood
--A low number of white
blood cells can make it
easier to get infections

Hair loss

Decreased ability of the
body to fight infection

Absence or decrease in the
number of sperm which
may be temporary or
permanent which may
decrease the ability to
have children

Abnormal hormone function
which may lower the level of salt
in the blood

Abdominal pain

Diarrhea

Fewer red blood cells and
platelets in the blood
-A low number of red blood cells
may make you feel tired and weak
-A low number of platelets may
cause you to bruise and bleed
more easily

Bleeding and inflammation of the
urinary bladder

Absence or decrease of monthly
periods which may be temporary
or permanent and which may
decrease the ability to have
children

Temporary blurred vision

Nasal stuffiness with IV infusions

Skin rash

Darkening of areas of the skin and
finger nails

Slow healing of wounds

Infections
Heart muscle damage which
may
occur with very high doses
and which
may be fatal

Abnormal heart rhythms

Damage and scarring of lung
tissue which may make you
short of breath

A new cancer or leukemia
resulting from this treatment

Damage or scarring of
urinary bladder tissue

Severe allergic reaction
which can be life-threatening
with shortness of breath, low
blood pressure, rapid heart
rate chills and fever

Infertility which is the
inability to have children

78
Risks and side effects related to dexrazoxane include those which are:

Likely Less Likely Rare but serious
Fewer white blood cells,
red blood cells and
platelets in the blood
-A low number of red
blood cells can make you
feel tired and weak
-A low number of white
blood cells can make it
easier to get infections
-A low number of platelets
causes you to bruise and
bleed more easily

Mild nausea and/or vomiting

Loss of appetite

A feeling of extreme tiredness or
not feeling well
Diarrhea

Increases in the blood of fats
(triglycerides) and an enzyme
made by the pancreas (amylase)

Temporary increases in the blood
of iron and decreases in the blood
of calcium and zinc

Damage to the skin if the
medication leaks from a vein

Thickening and hardening of the
veins or pain in the vein through
which the medication is given

Temporary elevation in the blood
of certain enzymes and bilirubin
found in the liver

It may take longer for the blood to
clot
A new cancer or leukemia
resulting from this treatment

79
Risks and side effects related to doxorubicin include those which are:

Likely Less Likely Rare but serious
Nausea

Vomiting

Temporary hair loss

Pink or red color to urine,
sweat, tears, saliva

Fewer white blood cells,
red blood cells and
platelets in the blood
-A low number of red
blood cells can make you
feel tired and weak
-A low number of white
blood cells can make it
easier to get infections
-A low number of platelets
causes you to bruise and
bleed more easily

Slight damage to the heart
muscle that is unlikely to
have any noticeable
effects on your heart
function

Inflammation and/or sores in the
mouth (and/or throat and /or
esophagus, the tube that leads
from the mouth to the stomach)
that may make swallowing
difficult and are painful (painful
mouth sores)

Damage to the heart muscle
which may make you tired, weak,
feel short of breath, and retain
fluid

Facial flushing

Fever/chills

Hives

High levels of uric acid in the
blood which could damage the
kidneys

Dark discoloration of the hands,
feet and under the fingernails with
possible separation of the nail
from the nail bed

Damage to the skin if the
medication leaks from a vein

Thickening and hardening of the
veins through which the
medication is given

Reddening reaction of the vein
through which the drug is given

Elevation in the blood of certain
enzymes found in the liver

Tearing and inflammation of the
eyes

Loss of appetite

Redness and burning at sites
which have received radiation in
the past

Diarrhea
Severe allergic reaction
which can be life-threatening
with shortness of breath, low
blood pressure and a rapid
heart rate

Ulceration of the lower
intestinal tract

An irregular heart beat
which can be life-
threatening

Severe damage to the heart
muscle which may lead to
severe heart failure

A new cancer or leukemia
resulting from this treatment

Doxorubicin can cause damage to your heart; your heart function will be tested during
therapy to watch for this possible side effect. If your doctors think it necessary, they will
stop giving you doxorubicin and give you a drug called dactinomycin instead.

80

Risks and side effects related to dactinomycin include those which are:

Likely Less Likely Rare but serious
Nausea

Vomiting

Temporary hair loss

Fewer white blood cells,
red blood cells and
platelets in the blood
-A low number of red
blood cells can make you
feel tired and weak
-A low number of white
blood cells can make it
easier to get infections
-A low number of platelets
causes you to bruise and
bleed more easily

Inflammation and/or ulceration
(rarely) of the lips, the mouth,
throat, esophagus, intestines or
rectum

Fever

Diarrhea and/or abdominal pain

Damage to the skin if the
medication leaks from a vein

Elevation in the blood of certain
enzymes found in the liver

Loss of appetite

Redness, burning or a darkening
of the skin at sites which have
received radiation in the past

A feeling of extreme tiredness,
weakness or not feeling well

Muscle aches and pains

Acne or other types of skin bumps

Lower levels of calcium in the
blood

A slowing of normal growth
Severe allergic reaction
which can be life-threatening
with shortness of breath, low
blood pressure and a rapid
heart rate

Inflammation or damage to
the liver which can be severe
and life-threatening and
which may lead to an
enlarged liver and spleen,
bleeding from the veins in
the esophagus (the passage
that leads from the throat to
the stomach), a yellow
appearing skin, and fluid
collection in the abdomen
which makes it look larger

Inflammation of the lungs
which could lead to chest
pain and discomfort

A new cancer or leukemia
resulting from this treatment

Risks and side effects related to etoposide include those which are:

Likely Less Likely Rare but serious
Nausea and vomiting

Loss of appetite Damage to the liver

Hair loss

A feeling of weakness or
tiredness

fewer red and white blood
cells and platelets in the
blood
-a low number of red
blood cells can make you
feel tired and weak
-a low number of white
blood cells can make it
easier to get infections
-a low number of platelets
causes you to bruise and
bleed more easily

Decreased blood pressure
during the infusion which may
require treatment
Severe allergic reaction
which can be life-threatening
with shortness of breath, low
blood pressure, rapid heart
rate chills and fever

Rashes

Diarrhea A new cancer or leukemia
resulting from this treatment
Pain in the abdomen
Severe rashes which can
result in loss of skin and
damage to mucous
membranes
Absence or decrease of
monthly periods which may
be temporary or permanent
and which may decrease the
ability to have children

Mouth sores
Tingling sensation or loss of
sensation in fingers or toes

A feeling of extreme tiredness
or weakness

The finger or toe nails may
loosen from their nail beds

Inflammation of the vein
through which the medication
was given

Chest pain
Damage to the heart muscle
which may make you feel
tired, weak, feel short of
breath, and retain fluid
81

82
Risks and side effects related to filgrastim (G-CSF) include those which are:

Likely Less Likely Rare but serious
Aching or pain in the
bones

Local irritation at the site
of the injection

Headache

Higher than normal
levels of liver enzymes
which may indicate liver
irritation or damage and
uric acid in the blood

A low number of
platelets in the blood
which may cause you to
bruise and bleed more
easily

Low fever

Enlargement of the
spleen which may cause
pain in the abdomen or
left shoulder

Worsening of skin rashes

Inflammation of a blood
vessel in the skin leading
to a raised purple rash
and bruising

Higher than normal
white blood count
Allergic reactions which can
be life-threatening with
shortness of breath, low blood
pressure, rapid heart rate, hives
and facial swelling. This
reaction is very rare and has
been associated mainly with
intravenous administration.

If you are known to have
sickle cell disease, filgrastim
may cause a sickle cell crisis.

Severe damage to the spleen
(an organ in the abdomen/belly
which stores blood cells)
which could lead to pain and
loss of blood into the abdomen
(belly) and may be life-
threatening

Difficulty breathing and lung
damage that may be due to the
white blood cells that are
stimulated by filgrastim
traveling to the lungs when
they are inflamed or infected

A blood disorder or leukemia
that has only been seen in
patients with certain immune
disorders who are treated for a
very long time

83
Risks and side effects related to ifosfamide include those which are:

Likely Less Likely Rare but serious
Nausea

Vomiting

Hair loss

Fewer white blood cells in
the blood.
-A low number of white
blood cells may make it
easier to get infections
-Decreased ability of the
body to fight infection

Absence or decrease in the
number of sperm which
may be temporary or
permanent which may
decrease the ability to
have children

Slight decrease in kidney
function
Drowsiness

Confusion

Depression

Loss of appetite

Diarrhea or constipation

Fewer red blood cells and
platelets in the blood
-A low number of red blood
cells may make you feel
tired and weak
-A low number of platelets
may cause you to bruise and
bleed more easily

Seizures

Abnormal hormone function
affecting levels of salt in the
blood and urine

Abnormal heart beat or
rhythm

Blood in the urine that is
only seen under the
microscope

Body loss of certain
important salts and minerals
(such as sodium, potassium,
phosphate and bicarbonate)
and retention of acids in the
blood

Failure of the ovaries to
function normally which
may be permanent and which
may decrease the ability to
have children

Inflammation and burning
along the vein where the
medicine is given

Elevation in the blood of
certain enzymes found in the
liver
Damage to brain tissue with
very high doses that may
lead to coma

Kidney failure or damage

Damage to the bladder
which can lead to large
amounts of blood in the
urine, pain and the urge to
urinate frequently and also
scarring of the bladder

A new cancer or leukemia
resulting from this treatment

Damage to heart muscle
which may make you tired,
weak, feel short of breath,
and retain fluid

Abnormal bone growth and
development

84
Risks and side effects related to mesna include those which are:

Likely Less Likely Rare but serious
Bad taste when taken by
mouth

Nausea

Vomiting

Stomach pain

Headache

Pain in arms, legs and joints

Tired feeling

Rash

Temporary low blood
pressure

Diarrhea

Fever

Facial flushing with red
cheeks

Nervousness

Dizziness

Confusion

Swelling around the eyes

Coughing

Rapid heart rate
Severe allergic reaction which can
be life-threatening with shortness
of breath, low blood pressure,
rapid heart rate chills and fever

Risks and side effects related to vincristine include those which are:

Likely Less Likely Rare but serious
Hair loss

Reversible nerve
problem that may
affect the way you
walk or the feelings in
your fingers or toes

Constipation
Jaw pain Complete stoppage of your intestinal
activity which can result in intestinal
blockage

Headache

Muscle weakness If the drug leaks out of the vein when
being administered it will cause damage
to nearby tissue

Pain and bloating in your
abdomen
Seizures
Numbness and tingling
Vocal cord paralysis
Wrist or foot drop
Difficulty breathing
Drooping eyelids
Inability to walk
Double vision, difficulty
seeing at night

Decreased ability to hear clearly

Hoarseness of your voice Damage to the nerve to the eye (optic
nerve) leading to decreased vision and
possible blindness

Difficulty sweating

Abnormal walk with foot
slapping
In combination with other chemotherapy
drugs: damage to the liver which can lead
to inflammation and/or scarring which
could lead to a yellow appearing skin,
and fluid collection in the abdomen
(belly) which makes it look larger

Difficulty with urination or
increase desire to urinate

Dizziness

Abnormal hormone function
which may lower the level of
salt in the blood

A mild drop in white blood
cells, red blood cells and
platelets in the blood
-a low number of red blood
cells can make you feel tired
and weak
-a low number of white
blood cells can make it
easier to get infections
-a low number of platelets
causes you to bruise and
bleed more easily

85

86
Radiation Risks:

Your doctor will discuss radiation therapy and the risks involved when you sign the consent
to have radiation therapy. In general, radiation therapy has been associated with side effects
which may include: temporary hair loss, nausea, vomiting, diarrhea, redness or dryness of
the skin, low blood counts, mouth sores and/or injury to tissues or organs that may be
included in the treatment field. Sterility is associated with ovarian or testicular irradiation.

Potential late effects of radiation therapy may include problems with soft tissue or bone
growth, vision problems, changes in endocrine function (low hormone levels), learning
disabilities or brain injury, and increased risk for developing another cancer. These late
effects depend on where in the body the radiation therapy is given, the age of the patient, and
the drugs and surgery given at the same time as part of the therapy.

87

APPENDIX B

SUPPORTIVE CARE

These are provided for institutional consideration. Investigator discretion should be used,
and individual considerations made for specific patient situations and institutional practices.
Care providers may refer also to Supportive Care of Children with Cancer, 2004 Third
Edition, Arthur R. Altman, M.D.

1) Venous Access
In order to facilitate safe administration of the required chemotherapy agents and support
medications Placement of a central venous access device, preferably a double lumen, is
strongly recommended. This will often require a surgical procedure under general
anesthesia, for which separate consent should be obtained.

2) Pneumocystis Carinii Prophylaxis
PCP prophylaxis with Bactrim® (TMP-SMX) is recommended for all, and required for
children less than one year of age, and those receiving pulmonary radiation. 5 mg/kg/day of
trimethoprim (maximum dose 320 mg/day) with 25 mg/kg/day sulfamethoxizole (maximum
dose 1600 mg/day) should be given divided b.i.d. on two or three consecutive days per week.
Note: Although not usually a problem, this combination may cause prolongation of bone
marrow suppression in some patients. If TMP-SMX is not tolerated either because of allergy
or myelosuppression, consider the use of Dapsone (2 mg/kg/day, maximum 100 mg/day) or
aerosolized pentamidine.

3) Hematopoietic Growth Factors
See Section 4 regarding use of Filgrastim (G-CSF).
Note: Use of Neulasta (pegfilgrastim) or GM-CSF (sargramostim) is not permitted.

4) Mucositis
A few simple remedies for mucositis are available, and all should be pursued before doses are
reduced. The incidence and severity of mucositis have been related to degree of pre-existing
mucosal disease and oral hygiene. Good mouth care, including use of mouth rinses such as
0.12% chlorhexidine gluconate should be considered.

Medications
Glutamine: Oral swish-and-swallow glutamine suspension at 2 g/m
2
swish-and-swallow
twice daily has been shown to reduce the severity and duration of mucositis associated with
chemotherapy and radiotherapy in a randomized controlled trial.
33
Glutamine powder is
available at low cost in health food stores. There may be a clinical study of a more palatable
glutamine preparation for which patients on this study will be eligible.

Sucralfate: Though its effectiveness is controversial, sucralfate suspension 1 gram/10 mL
(40-80 mg/kg/day, max 1 gram per dose) swish-and-swallow q.i.d. may reduce the
symptoms or severity of mucositis from chemotherapy and radiation therapy.

88
5) Blood Product Support

Irradiation
Blood products should be irradiated following the current FDA guidelines found at:
http://www.fda.gov/cber/gdlns/gamma.htm

Abstract (if available)

Abstract Intergroup Ewing sarcoma study INT-0091 demonstrated that a regimen of alternating vincristine-doxorubicin-cyclophosphamide (VDC) and ifosfamide-etoposide (IE) was superior to vincristine-doxorubicin-cyclophosphamide alone. The 5-drug regimen is the North American standard therapy for localized Ewing sarcoma. COG-AEWS0031 investigated interval compression of the drug combination vs. standard chemotherapy for localized Ewing sarcoma and showed that patients treated with interval compressed 5-drug combination had a superior event free survival and overall survival when compared to standard chemotherapy. Addition of new active drug combinations to standard chemotherapy is a potential strategy to improve the outcome of patients with Ewing sarcoma. This pilot clinical trial will investigate the addition of vincristine-topotecan-cyclophosphamide (VTC) to a treatment protocol utilizing interval compression of VDC and IE for patients with localized Ewing sarcoma family of tumors (ESFT). If feasible, this regimen will become the experimental arm in a planned Group-wide phase III clinical trial in patients with Ewing Sarcoma.

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