# Outpatient and Home Chemotherapy with Novel Local Control Strategies in Desmoplastic Small Round Cell Tumor

Authors: Dolly Aguilera; Andrea Hayes-Jordan; Peter Anderson; Shiao Woo; Margaret Pearson; Holly Green
Journal: Sarcoma
 (2008)

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## Abstract

Desmoplastic Small Round Cell Tumor (DSRCT) has a very poor prognosis. This report illustrates novel chemotherapy and local control interventions in a 5-year old patient. The patient was treated in the outpatient setting, achieved remission, with excellent quality of life. The patient presented with massive ascites and >1000 abdominal tumors. Neoadjuvant chemotherapy included vincristine(1.5mg/m2), ifosfamide (3g/m2/day×3), dexrazoxane/doxorubicin (750/75mg/m2), and etoposide (150mg/m2). Continuous hyperthermic peritoneal perfusion (CHPP) with cisplatin (100mg/m2) was given after extensive cytoreductive surgery. This was followed by irinotecan (10mg/m2/day×5×2weeks) + temozolomide monthly × 2, then abdominal radiation 30 Gy with simultaneous temozolomide (100mg/m2/day×5). A total of 12 cycles of irinotecan and temozolamide were given. Except for initial chemotherapy, subsequent courses were in the outpatient setting. Focal retroperitoneal relapse at 18 months was treated with IMRT with bevacizumab (5 mg/kg) and 2 perihepatic metastases with radio frequency ablation/cryoablation followed by chronic outpatient maintenance chemotherapy (valproic acid, cyclophosphamide, and rapamycin).  Almost 2 years from diagnosis, the patient maintained an excellent quality of life. This is a novel approach to the treatment of children with massive abdomino-pelvic DSRCT.


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## Body

## 1. Introduction

DSRCT is an aggressive neoplasm usually involving numerous peritoneal metastases. It can also occur in different lo-cations including the intrathoracic cavity, pleura, paratesticular,
and soft tissues. A specific recurringt(11;22) translocation involving EWS and
WT-1 is a characteristic [1]. Since the initial description of
DSRCT by Gerald and Rosai [2] in 1991, significant progress has
been made in its pathologic identification and diagnosis. However, despite
multiple treatment strategies among them, several chemotherapy regimens active
for Ewing's sarcoma, aggressive debulking surgery,
whole abdominal radiation, high-dose chemotherapy with autologous stem cell
transplant, DSRCT survival has not significantly improved. Despite much time in the hospital and
morbidity of interventions, durable remissions remain rare. Preliminary data
supports the combination of standard treatment modalities withcontinuous hyperthermic
peritoneal perfusion (CHPP) in adult patients with peritoneal carcinomatosis [3–6]. Thus, CHPP may be a rational approach
to improve local control of patients with DSRCT [7]. Experience with active chemotherapy agents for
DSRCT in the outpatient clinic and also home infusion settings are presented
here.


## 2. Case History

A 5-year old patient presented to an outside
institution with one-week history of abdominal pain and severe constipation not
improved with laxatives. Worsening of symptoms and abdominal distention prompted
additional evaluation. Abdominal CT scan demonstrated extensive peritoneal masses
(6 cm right lower abdomen; 5 cm between rectum and bladder, 8 cm pelvic floor
above the bladder), peritoneal and omental implants (estimated number of
metastases >1000), and massive ascites. There were many perihepatic lesions,
but no obvious tumors within the liver. The patient was referred to MD Anderson
Cancer Center, Children’s Cancer Hospital. An exploratory
laparotomy was done for biopsy and staging purposes; ascites was drained and a
temporary peritoneal catheter for ascites removal was placed. The tumor was
limited to the abdominal cavity. Other organs had no evidence of disease.
Histologic exam of the ascities fluid demonstrated some DSRCT cells in a
background of lymphocytosis.Pathology of tumor biopsies (see Figure1) showed features of a highly anaplastic and somewhat pleomorphic small blue
cell malignancy. The immunohistochemical profile included: EMA 4+ in 75% of neoplastic cells with cytoplasmic
(granular) pattern; Vimentin: 4+ in 95% of neoplastic cells with cytoplasmic
finely and coarsely granular pattern, CD-99/Myc-2 2+ immunoreactivity in 30% of
neoplastic cells cytoplasmic and granular pattern, Desmin 4+ in 95% of tumor cells, Myogenin
(-), SMA (-), Bcl-2 (-), CD3 (-), CD20 (-), Synaptophysin (-), Chromogranin
(-). Cytogenetic analysis confirmed the presence of t(11;22)(p15;q12)by FISH characteristic
of DSRCT.Peritoneal nodule of DSRCT at diagnosis. Nodules are composed of fibrocollagenous
tissue and irregular islands of malignant undifferentiated small round
cells. Immunoperoxidase stains (not
shown) in this case were strongly positive for EMA, vimentin, and desmin,
partially positive for CD99 and negative for synaptophysin, chromogranin,
myogenin, SMA, Bcl-2, CD3, and CD20.
Cytogenetic analysis demonstrated t(11;22)(p15;q12). Magnification: (a) × 10, (b) × 40, (c) high
power.
(a)(b)(c)


### 2.1. Preadjuvant Chemotherapy Treatment

Figure2 shows a sequence of Neoadjuvant
and adjuvant chemotherapy. First cycle was vincristine (1.5 mg/m2), cyclophosphamide (2.2 g/m2), and doxorubicin (75 mg/m2)
as an inpatient. Subsequent chemotherapy
was outpatient and used a modified “VIDE” regimen similar to EuroEwings protocols every
three weeks in 4 cycles. Vincristine 1.5 mg/m2 was followed by
dexrazoxane (750 mg/m2 IV over 15 minutes) + doxorubicin (75 mg/m2 IV over 15 minutes) and etoposide (150 mg/m2 IV over 1 hour). Ifosfamide
(3 g/m2) was mixed with MESNA (3 g/m2/day) in volume of
240 mL normal saline and given as a continuous infusion × 3 days (total dose 9 g/m2) followed by 1 day of MESNA (3 g/m2). Pegfilgrastim was
given after completion of MESNA when port was deaccessed by the home health
nurse.Figure 2
Outpatient neoadjuvant and adjuvant chemotherapy plan for DSRCT. After initial diagnosis and treatment of peritoneal, abdominal and
pelvic disease, systemic chemotherapy
agents were administered on an outpatient basis followed by local control with
cytoreductive surgery + CHPP with cisplatin, then whole abdomen radiation with
temozolomide as a radiation sensitizer, followed by temozolomide and
irinotecan. Outpatient therapy was 15
months.Day 1 chemotherapy was given in the
outpatient clinic; ifosfamide infusions were done at home with bag
changes by home health nursing.
The patient had excellent performance and attended elementary school. Just
prior to local control surgery, an additional cycle consisting of vincristine
and liposomal doxorubicin (40 mg/m2 IV over 3 hours with hands and
feet on ice to reduce risk of palmar/plantarerythrodysesthesia) was administered. Total anthracycline dose was 415 mg/m2.


### 2.2. Local Control Phase of Therapy: CHPP and Radiation

Five months from initial
presentation, and after approval by the institutional review board, the patient
underwent aggressive cytoreductive surgery including greater and lesser
omentectomy, cholecystectomy and partial peritonectomy and removal of 402
metastatic nodules.At the end of the surgical procedure,
cisplatin 100 mg/m2 at 40–42°C was continuously perfused
in the peritoneal cavity. CHPP (Figure 3) consisted of the placement of 7 temperature
probes: (1) ligament of Treitz, (2) right lobe of the liver, (3) right upper
quadrant, (4) left upper quadrant, (5) right lower quadrant, (6) left lower
quadrant, and (7) sigmoid colon mesentery. The abdomen was then closed
temporarily to secure the inflow and outflow cannulas. A Y-shaped inflow cannula was placed above
the liver, and a pelvic drain was placed in the pelvis.Figure 3
Continuous hyperthermic peritoneal perfusion (CHPP). The CHPP procedure involves placing
temperature probes, inflow and outflow cannulas, and continuous perfusion
of plasmalyte followed by cisplatin
containing chemotherapy as the perfusate at 41-42°C. To achieve this, the inflow was usually about
45°C. Manual agitation of the closed abdomen was done for 1.5 hours
to ensure that all peritoneal surfaces were exposed to the cisplatin.Plasmalyte was perfused for 15 to 20
minutes to establish equivalent temperatures. When average temperatures of 40°C
were established in all portions of the abdomen,cisplatin 100 mg/m2 was added to the perfusate simultaneous with the
beginning of an intravenous infusion of sodium disulfate. The abdomen was continuously
agitated for 90 minutes, temperatures were monitored frequently, and agitation
was adjusted according to the temperature of each probe. The temperature of the inflow and the thermomistor
was 45°C. Temperature in the intra-abdominal
probes was about 41-42°C. The volume was 2.5 liters. Flow rate was 700 mL/minute throughout the 1.5
hour CHPP procedure. Cisplatin was drained, and then two liters of Plasmalyte at
room temperature were infused to rinse cisplatin from the peritoneal cavity. Abdomen
was reopened and inspected. Gastrostomy and jejunostomy tubes were placed in
anticipation of enteral nutrition in the post-operatory period. The patient had
a rapid recovery and was discharged from the hospital to home 7 days after
surgery.Pathology evaluation from peritoneal tumor
nodules reported minimal residual malignant small tumor cells in most of the
specimens consistent with microscopic residual disease.


### 2.3. Adjuvant DSRCT Chemotherapy and Radiosensitization Program

Outpatient and home chemotherapy were provided before and during
radiation (6 months from diagnosis) and then for an additional 8 cycles until
14 months after diagnosis. Regimen was similar to that reported by Wagner et al.
[8]. Temozolamide (100 mg/m2/day × 5 days) and irinotecan (10 mg/m2/day × 5 days × 2 weeks) for
2 four-week cycles. During total abdominal radiation (3 Gy × 10 fractions; total
30 Gy and 15 Gy to the liver/kidneys) irinotecan was not given and only temozolomide
(100 mg/m2/dose × 5 days × 2 cycles) was provided. After radiation, 8 cycles of temozolomide +
irinotecan were given. Day 1: temozolomide and irinotecan were given in the
outpatient clinic each month. Days 2–5 and 8–12: irinotecan chemotherapy
infusions were done at home (after school) using home health nursing.The patient tolerated this
chemotherapy well and had one, brief hospitalization for fever and neutropenia.
He was able to attend elementary school with almost perfect attendance.


### 2.4. Relapse: Additional Local Control with IMRT,  then Radio Frequency Ablation + Cryoablation

Although the patient continued to be
healthy, attend school, and had no symptoms, routine PET-CT done 2 months after
completion of therapy showed five FDG avid areas (Figure4). All were just outside
of the peritoneum and at edge or outside prior radiation fields: two adjacent
posterior perihepatic, one at the dome of the right diaphragm, and 2
retroperitoneal pericaval nodes. IMRT
(1.5 Gy in 15 fractions; total 45 Gy) was given to the retroperitoneal disease.
Radiosensitization was with temozolomide (75 mg/m2/day × 5 days × 2
weeks), bevacizumab (5 mg/kg every 2 weeks × 3 doses), valproate (500 mg/m2/day
divided BID), and rapamycin (2 mg/m2/day). The patient tolerated radiotherapy
well and had no side effects.Figure 4
PET-CT fusion imaging. (a) Residual uptake
in the peritoneal implants after 2 cycles of therapy, SUV 3. (b) No evidence of
FDG avid disease after cytoreductive therapy. (c) Relapse in the perihepatic
space including dome of the liver (SUV 2.8) and retroperitoneal nodes (SUV 5).He was reimaged and the adjacent perihepatic
lesions had increased in size from 3.0× 1.5 cm to approximately 3.8 × 2.6 cm and
from 3.3 × 1.3 cm to 4.3 × 2.2 cm; there was no change in size of the 1 cm dome
of right diaphragm lesion. To destroy cells in the perihepatic nodules and increase
chance of mounting an immune response, both radio frequency ablation and
cryoablation were used (Figure 5). Under
direct CT fluoroscopic guidance, a radio frequency ablation (RFA) electrode
(RITA system) was used to heat the tumor to 42-43°C for 30 minutes,
then each lesion was frozen using a cryoablation probe (PERC-17; Endocare) for
2 cycles of freezing (5–10 minutes) and thawing (5–8 minutes). The patient tolerated
the procedure well and was observed in the hospital overnight. He had no side
effects from the procedure except for some skin reaction and scab which
resolved in 2 weeks.Radio frequency ablation and cryoablation procedure. Under direct CT fluoroscopic guidance, an RFA electrode was advanced
into the perihepatic lesions. These were heated from 42°C to 43°C for 30 minutes (a) and (b) then a cryoablation probe was advanced and 2 cycles of
freeze and thaw for 8–10 minutes (c).
(a)(b)(c)


### 2.5. Chronic Adjuvant Chemotherapy Program and Followup

The patient received a regimen of
valproate (250 mg BID), rapamycin (2 mg daily), and sorafenib (200 mg BID) and
chemotherapy similar to that reported by Casanova et al. [9], vinorelbine (25 mg/m2 IV monthly)
and oral cyclophosphamide (25 mg daily) (see Figure 6). Sorafenib and vinorelbine were
discontinued because of significant diarrhea (see treatment schema in Figure 6). The patient attended school full time
without symptoms.Figure 6
Schema for local control
of relapse foci and continuation adjuvant therapy. Radiation in combination with
bevacizumab was used to pericaval disease.
Localized perihepatic lesions were treated with a combination of RFA and
cryoablation. These measures were followed with a chronic adjuvant regimen.For almost 2 years from diagnosis of massive
disease at DSRCT, this patient has had only 32 days of hospitalization
including initial admission of 18 days, 3 days for hydration, 1 episode for
hematuria, 2 days for fever and neutropenia, 7 days for CHPP surgery, and 1
overnight observation for RFA + cryoablation.
He will continue on a maintenance chemotherapy regimen and be followed
with PET-CT fusion imaging every 3 months.


## 2.1. Preadjuvant Chemotherapy Treatment

Figure2 shows a sequence of Neoadjuvant
and adjuvant chemotherapy. First cycle was vincristine (1.5 mg/m2), cyclophosphamide (2.2 g/m2), and doxorubicin (75 mg/m2)
as an inpatient. Subsequent chemotherapy
was outpatient and used a modified “VIDE” regimen similar to EuroEwings protocols every
three weeks in 4 cycles. Vincristine 1.5 mg/m2 was followed by
dexrazoxane (750 mg/m2 IV over 15 minutes) + doxorubicin (75 mg/m2 IV over 15 minutes) and etoposide (150 mg/m2 IV over 1 hour). Ifosfamide
(3 g/m2) was mixed with MESNA (3 g/m2/day) in volume of
240 mL normal saline and given as a continuous infusion × 3 days (total dose 9 g/m2) followed by 1 day of MESNA (3 g/m2). Pegfilgrastim was
given after completion of MESNA when port was deaccessed by the home health
nurse.Figure 2
Outpatient neoadjuvant and adjuvant chemotherapy plan for DSRCT. After initial diagnosis and treatment of peritoneal, abdominal and
pelvic disease, systemic chemotherapy
agents were administered on an outpatient basis followed by local control with
cytoreductive surgery + CHPP with cisplatin, then whole abdomen radiation with
temozolomide as a radiation sensitizer, followed by temozolomide and
irinotecan. Outpatient therapy was 15
months.Day 1 chemotherapy was given in the
outpatient clinic; ifosfamide infusions were done at home with bag
changes by home health nursing.
The patient had excellent performance and attended elementary school. Just
prior to local control surgery, an additional cycle consisting of vincristine
and liposomal doxorubicin (40 mg/m2 IV over 3 hours with hands and
feet on ice to reduce risk of palmar/plantarerythrodysesthesia) was administered. Total anthracycline dose was 415 mg/m2.


## 2.2. Local Control Phase of Therapy: CHPP and Radiation

Five months from initial
presentation, and after approval by the institutional review board, the patient
underwent aggressive cytoreductive surgery including greater and lesser
omentectomy, cholecystectomy and partial peritonectomy and removal of 402
metastatic nodules.At the end of the surgical procedure,
cisplatin 100 mg/m2 at 40–42°C was continuously perfused
in the peritoneal cavity. CHPP (Figure 3) consisted of the placement of 7 temperature
probes: (1) ligament of Treitz, (2) right lobe of the liver, (3) right upper
quadrant, (4) left upper quadrant, (5) right lower quadrant, (6) left lower
quadrant, and (7) sigmoid colon mesentery. The abdomen was then closed
temporarily to secure the inflow and outflow cannulas. A Y-shaped inflow cannula was placed above
the liver, and a pelvic drain was placed in the pelvis.Figure 3
Continuous hyperthermic peritoneal perfusion (CHPP). The CHPP procedure involves placing
temperature probes, inflow and outflow cannulas, and continuous perfusion
of plasmalyte followed by cisplatin
containing chemotherapy as the perfusate at 41-42°C. To achieve this, the inflow was usually about
45°C. Manual agitation of the closed abdomen was done for 1.5 hours
to ensure that all peritoneal surfaces were exposed to the cisplatin.Plasmalyte was perfused for 15 to 20
minutes to establish equivalent temperatures. When average temperatures of 40°C
were established in all portions of the abdomen,cisplatin 100 mg/m2 was added to the perfusate simultaneous with the
beginning of an intravenous infusion of sodium disulfate. The abdomen was continuously
agitated for 90 minutes, temperatures were monitored frequently, and agitation
was adjusted according to the temperature of each probe. The temperature of the inflow and the thermomistor
was 45°C. Temperature in the intra-abdominal
probes was about 41-42°C. The volume was 2.5 liters. Flow rate was 700 mL/minute throughout the 1.5
hour CHPP procedure. Cisplatin was drained, and then two liters of Plasmalyte at
room temperature were infused to rinse cisplatin from the peritoneal cavity. Abdomen
was reopened and inspected. Gastrostomy and jejunostomy tubes were placed in
anticipation of enteral nutrition in the post-operatory period. The patient had
a rapid recovery and was discharged from the hospital to home 7 days after
surgery.Pathology evaluation from peritoneal tumor
nodules reported minimal residual malignant small tumor cells in most of the
specimens consistent with microscopic residual disease.


## 2.3. Adjuvant DSRCT Chemotherapy and Radiosensitization Program

Outpatient and home chemotherapy were provided before and during
radiation (6 months from diagnosis) and then for an additional 8 cycles until
14 months after diagnosis. Regimen was similar to that reported by Wagner et al.
[8]. Temozolamide (100 mg/m2/day × 5 days) and irinotecan (10 mg/m2/day × 5 days × 2 weeks) for
2 four-week cycles. During total abdominal radiation (3 Gy × 10 fractions; total
30 Gy and 15 Gy to the liver/kidneys) irinotecan was not given and only temozolomide
(100 mg/m2/dose × 5 days × 2 cycles) was provided. After radiation, 8 cycles of temozolomide +
irinotecan were given. Day 1: temozolomide and irinotecan were given in the
outpatient clinic each month. Days 2–5 and 8–12: irinotecan chemotherapy
infusions were done at home (after school) using home health nursing.The patient tolerated this
chemotherapy well and had one, brief hospitalization for fever and neutropenia.
He was able to attend elementary school with almost perfect attendance.


## 2.4. Relapse: Additional Local Control with IMRT,  then Radio Frequency Ablation + Cryoablation

Although the patient continued to be
healthy, attend school, and had no symptoms, routine PET-CT done 2 months after
completion of therapy showed five FDG avid areas (Figure4). All were just outside
of the peritoneum and at edge or outside prior radiation fields: two adjacent
posterior perihepatic, one at the dome of the right diaphragm, and 2
retroperitoneal pericaval nodes. IMRT
(1.5 Gy in 15 fractions; total 45 Gy) was given to the retroperitoneal disease.
Radiosensitization was with temozolomide (75 mg/m2/day × 5 days × 2
weeks), bevacizumab (5 mg/kg every 2 weeks × 3 doses), valproate (500 mg/m2/day
divided BID), and rapamycin (2 mg/m2/day). The patient tolerated radiotherapy
well and had no side effects.Figure 4
PET-CT fusion imaging. (a) Residual uptake
in the peritoneal implants after 2 cycles of therapy, SUV 3. (b) No evidence of
FDG avid disease after cytoreductive therapy. (c) Relapse in the perihepatic
space including dome of the liver (SUV 2.8) and retroperitoneal nodes (SUV 5).He was reimaged and the adjacent perihepatic
lesions had increased in size from 3.0× 1.5 cm to approximately 3.8 × 2.6 cm and
from 3.3 × 1.3 cm to 4.3 × 2.2 cm; there was no change in size of the 1 cm dome
of right diaphragm lesion. To destroy cells in the perihepatic nodules and increase
chance of mounting an immune response, both radio frequency ablation and
cryoablation were used (Figure 5). Under
direct CT fluoroscopic guidance, a radio frequency ablation (RFA) electrode
(RITA system) was used to heat the tumor to 42-43°C for 30 minutes,
then each lesion was frozen using a cryoablation probe (PERC-17; Endocare) for
2 cycles of freezing (5–10 minutes) and thawing (5–8 minutes). The patient tolerated
the procedure well and was observed in the hospital overnight. He had no side
effects from the procedure except for some skin reaction and scab which
resolved in 2 weeks.Radio frequency ablation and cryoablation procedure. Under direct CT fluoroscopic guidance, an RFA electrode was advanced
into the perihepatic lesions. These were heated from 42°C to 43°C for 30 minutes (a) and (b) then a cryoablation probe was advanced and 2 cycles of
freeze and thaw for 8–10 minutes (c).
(a)(b)(c)


## 2.5. Chronic Adjuvant Chemotherapy Program and Followup

The patient received a regimen of
valproate (250 mg BID), rapamycin (2 mg daily), and sorafenib (200 mg BID) and
chemotherapy similar to that reported by Casanova et al. [9], vinorelbine (25 mg/m2 IV monthly)
and oral cyclophosphamide (25 mg daily) (see Figure 6). Sorafenib and vinorelbine were
discontinued because of significant diarrhea (see treatment schema in Figure 6). The patient attended school full time
without symptoms.Figure 6
Schema for local control
of relapse foci and continuation adjuvant therapy. Radiation in combination with
bevacizumab was used to pericaval disease.
Localized perihepatic lesions were treated with a combination of RFA and
cryoablation. These measures were followed with a chronic adjuvant regimen.For almost 2 years from diagnosis of massive
disease at DSRCT, this patient has had only 32 days of hospitalization
including initial admission of 18 days, 3 days for hydration, 1 episode for
hematuria, 2 days for fever and neutropenia, 7 days for CHPP surgery, and 1
overnight observation for RFA + cryoablation.
He will continue on a maintenance chemotherapy regimen and be followed
with PET-CT fusion imaging every 3 months.


## 3. Results

### 3.1. Effective Chemotherapy as an Outpatient

Once ascites improved after initial
chemotherapy cycle, subsequent cycles were given in the outpatient clinic. For 13
out of 14 cycles, only day 1 was given at the major medical center, days 2–4
ifosfamide or 2–12 irinotecan were given at home using home infusion services.Response to initial chemotherapy
(Table1) was evaluated with abdominal CT scans interpreted as a very good partial response (Figure 4), more than 50% reduction
of the perihepatic, pelvic, and omental implants when compared with initial CT imaging
studies. After one cycle of chemotherapy, PET scan demonstrated diffuse nodules
and less ascites throughout the abdomen. PET-CT demonstrated low-grade FDG
activity (maximal SUV 3). After completion of 4 months of VIDE, PET scan continued
to demonstrate low-FDG uptake in the perihepatic implant with maximum SUV
measured at 3 (stable disease). Other
nodules did not show significant uptake probably because of small size (<1 cm). PET scan after cytoreductive surgery, CHPP, and one cycle of temozolamide
/irinotecan showed residual activity over the dome of the right lobe of the
liver may
be post treatment-related or post-surgical in nature. After completion of abdominal radiation and temozolomide with irinotecan
(6 cycles), there was no evidence of FDG avid disease. This was considered a
clinical complete remission.Table 1
Outpatient DSRCT chemotherapy: doses and schedule.
AgentDoseRouteCommentsPreadjuvant phase of therapy (every 3 weeks× 4 cycles)Vincristine1.5 mg/m2iv over 2–15 minutesMax dose 2 mg; day 1 onlyEtoposide150 mg/m2iv over 1 hourDay 1 onlyDexrazoxane750 mg/m2iv over 15 minutesJust before doxorubicinDoxorubicin75 mg/m2iv over 15 minutesDay 1 onlyIfosfamide3 g/m2iv daily× 3Continuous infusion. Mix+ MESNA3 g/m2iv daily× 4with MESNA in 240–360 mL NS days 1, 2, 3.MESNA only day 4 (portable pump as outpatient)CHPP phaseCisplatin100 mg/m2IntraperitonealAs continuous peritoneal perfusion at 42°C × 1.5 hrRadio sensitization during RTTemozolomide75 mg/m2poDaily× 5 × 2 weeksBevacizumab5 mg/kgivq2 weeks× 2 doses begin before RTPre-RT (2 cycles) and post-RT (10 cycles)Temozolomide100 mg/m2poDaily× 5 each monthIrinotecan10 mg/m2ivDaily× 5 × 2 weeks each month; may do as home infusionsChronic continuation chemotherapyValproate500 mg/m2poDaily; divide BID monitor level <100Rapamycin2 mg/m2poDaily round to nearest mgCyclophosphamide25 mgpoIf >1.5 m2 may give 50 mg daily. Monitor cbc


### 3.2. Excellent Quality of Life during Outpatient  and Home Chemotherapy Program

Except for the initial chemotherapy, the
treatment regimen for this patient was in the outpatient or home setting,
allowing him to have excellent quality of life. This allowed school attendance and play at
home. Generally home ifosfamide bag changes or irinotecan infusions could be
done after  school.


### 3.3. Approach to High-Risk Status: Surveillance  Detects Recurrence before Symptoms

Because the patient had a high risk
of recurrence, based on the initial presentation with massive ascities and very
large number of peritoneal implants, close monitoring for relapse was necessary
with PET-CT imaging fusion every 12
weeks during and after therapy. This resulted in detection of recurrence before
appearance of clinical symptoms. The PET-CT also provided information useful in
IMRT treatment planning.Chronic adjuvant chemotherapy: well tolerated.The current therapy designed to treat
an Ewing's family of tumor using agents
compatible with outpatient or home therapy that could be given for months to
years. Because of high-risk status, a long term therapy is planned. The
toxicity has been with minimal with two episodes of fever and neutropenia or illness
associated with chemotherapy administration to date.


## 3.1. Effective Chemotherapy as an Outpatient

Once ascites improved after initial
chemotherapy cycle, subsequent cycles were given in the outpatient clinic. For 13
out of 14 cycles, only day 1 was given at the major medical center, days 2–4
ifosfamide or 2–12 irinotecan were given at home using home infusion services.Response to initial chemotherapy
(Table1) was evaluated with abdominal CT scans interpreted as a very good partial response (Figure 4), more than 50% reduction
of the perihepatic, pelvic, and omental implants when compared with initial CT imaging
studies. After one cycle of chemotherapy, PET scan demonstrated diffuse nodules
and less ascites throughout the abdomen. PET-CT demonstrated low-grade FDG
activity (maximal SUV 3). After completion of 4 months of VIDE, PET scan continued
to demonstrate low-FDG uptake in the perihepatic implant with maximum SUV
measured at 3 (stable disease). Other
nodules did not show significant uptake probably because of small size (<1 cm). PET scan after cytoreductive surgery, CHPP, and one cycle of temozolamide
/irinotecan showed residual activity over the dome of the right lobe of the
liver may
be post treatment-related or post-surgical in nature. After completion of abdominal radiation and temozolomide with irinotecan
(6 cycles), there was no evidence of FDG avid disease. This was considered a
clinical complete remission.Table 1
Outpatient DSRCT chemotherapy: doses and schedule.
AgentDoseRouteCommentsPreadjuvant phase of therapy (every 3 weeks× 4 cycles)Vincristine1.5 mg/m2iv over 2–15 minutesMax dose 2 mg; day 1 onlyEtoposide150 mg/m2iv over 1 hourDay 1 onlyDexrazoxane750 mg/m2iv over 15 minutesJust before doxorubicinDoxorubicin75 mg/m2iv over 15 minutesDay 1 onlyIfosfamide3 g/m2iv daily× 3Continuous infusion. Mix+ MESNA3 g/m2iv daily× 4with MESNA in 240–360 mL NS days 1, 2, 3.MESNA only day 4 (portable pump as outpatient)CHPP phaseCisplatin100 mg/m2IntraperitonealAs continuous peritoneal perfusion at 42°C × 1.5 hrRadio sensitization during RTTemozolomide75 mg/m2poDaily× 5 × 2 weeksBevacizumab5 mg/kgivq2 weeks× 2 doses begin before RTPre-RT (2 cycles) and post-RT (10 cycles)Temozolomide100 mg/m2poDaily× 5 each monthIrinotecan10 mg/m2ivDaily× 5 × 2 weeks each month; may do as home infusionsChronic continuation chemotherapyValproate500 mg/m2poDaily; divide BID monitor level <100Rapamycin2 mg/m2poDaily round to nearest mgCyclophosphamide25 mgpoIf >1.5 m2 may give 50 mg daily. Monitor cbc


## 3.2. Excellent Quality of Life during Outpatient  and Home Chemotherapy Program

Except for the initial chemotherapy, the
treatment regimen for this patient was in the outpatient or home setting,
allowing him to have excellent quality of life. This allowed school attendance and play at
home. Generally home ifosfamide bag changes or irinotecan infusions could be
done after  school.


## 3.3. Approach to High-Risk Status: Surveillance  Detects Recurrence before Symptoms

Because the patient had a high risk
of recurrence, based on the initial presentation with massive ascities and very
large number of peritoneal implants, close monitoring for relapse was necessary
with PET-CT imaging fusion every 12
weeks during and after therapy. This resulted in detection of recurrence before
appearance of clinical symptoms. The PET-CT also provided information useful in
IMRT treatment planning.Chronic adjuvant chemotherapy: well tolerated.The current therapy designed to treat
an Ewing's family of tumor using agents
compatible with outpatient or home therapy that could be given for months to
years. Because of high-risk status, a long term therapy is planned. The
toxicity has been with minimal with two episodes of fever and neutropenia or illness
associated with chemotherapy administration to date.


## 4. Discussion

In this report, we have shown a child
with high-risk DSRCT with massive disseminated peritoneal DSRCT implants who had
complete response and sustained a remission for  21 months following therapy
with a carefully designedmultimodality outpatient and home treatment plan.DRSCT has a 15% overall survival at 5 years [10].Patients presenting with abdominal disease typically are in an advanced
stage, with large masses and/or extensive seeding in the visceral and parietal
peritoneal layers. Thus, DSRCT in the abdomen is almost always disseminated
regionally. The presence of the translocation t(11 : 22) (p13 : q12) involving fusion
of the Ewing sarcoma gene (EWS) and the Wilm’s tumor gene (WT1) provides the
confirmation of diagnosis [1, 11].Chemotherapy agents with known
activity in DSRCT are very similar to those active in Ewing Sarcoma. Both tumors
share an EWS fusion protein and may also share molecular mechanisms
facilitating proliferation and survival pathways. Alkalyting agents such as cyclophosphamide
and ifosfamide are important components of therapy. Currently, a well-recognized treatment schema
has been reported by Kushner et al. [12]
who described results in 12 DSRCT patients. This intensive alkylator-based
therapy used cyclophosphamide, doxorubicin, vincristine alternating with
ifosfamide and etoposide. Its
combination with other treatment modalities such as surgery, radiation, autologous
stem cell rescue, or the combination of all of the above was used. The median survival
time was 19 months. For those achieving complete response, the median followup in
this series was 22 months, about the same as our patient. The toxicity for this
regimen can be substantial and often includes hospitalization not only for
chemotherapy, but also fevers associated with myelosupression and mucositis.
Our outpatient and home program had significantly less hospitalization and very
tolerable side effects. It permitted routine school attendance; play activities
were possible with an excellent quality of life.In our patient, ifosfamide/mesna as a continuous infusion as
previously described by Skubitz et al. [13], was well tolerated and allowed
treatment in the outpatient setting. No hydration is required. Since a small
volume (e.g., 240–360 mL/day) can be infused, this permits a normal pattern of
sleep. Irinotecan activity in sarcoma has been shown by Bisogno et al. [14] and Wagner et al. [8]. We also have observed high activity
of the temozolomide + irinotecan combination in relapsed Ewing’s sarcoma and 2
previous patients with DSRCT [15]. Rossof and Bayliff described successful responses in DSRCT cases to
irinotecan [16]. The toxicity of temozolomide and
irinotecan was very low. Our patient did not experienced documented infections;
home infusions of irinotecan were routine and done after school.Epigenetic alterations of DSRCT are
probable since EWS is associated with responses to such agents. For example, the effects of histone deacetylase (HDAC) inhibitors in Ewing’s
family tumors was recently described by Sakimura et al. [17]. This group showed expression of
the EWS-Fli1 fusion RNA and fusion protein was inhibited with desipeptide. Recent
preliminary work shows that both HDAC and mTOR inhibitors are promising not only for EWS, but
also DSRCT [18–20].
Low dose of cyclophosphamide has activity in pediatric sarcoma [9]. We have used this information in
the design of a chronic, well-tolerated outpatient adjuvant therapy in our DSRCT
patient.Immuno-histochemistry studies revealed
in several intra-abdominal DSRCT
specimens, upregulation in tumor cells of platelet derived growth factor AB chain and platelet derived
growth factor alpha receptor [21].
Perhaps these findings support additional contributions towards tumor
survival and/or apoptosis resistance. Thus
sorafenib, amultikinase inhibitor that directly inhibits the autophosphorylation of several
receptor tyrosine kinases including PDGFR beta, and c-kit may have additional
activity beyond VEGF receptor inhibition [22].Local control is important in DSRCT [10]. In our patient local control measures
included surgery with CHPP [5–7, 23], abdominal radiation with radiosensitizing
chemotherapy during the first cycle (temozolamide) and with bevacizumab during
radiation for relapse [24].
The initial role of surgery in patients with extensive intra-abdominal
disease is often limited to biopsies; after chemotherapy response this is followed
by a debulking procedure. Saab et al. [25]reported a series of patients with
abdominopelvic DRSCT with incomplete resection, in which total surgical
resection was not feasible; outcome was poor.Aggressive cytoreductive surgery is
currently accepted to have a primary role in the achievement of prolongedsurvival of some malignancies involving the peritoneum [4, 6].
In DSRCT Lal reported 3-year OS was 58% in gross total resection in
comparison with 0% in the nonresection cohort [10].
Other therapeutic modalities such as CHPP have been found to significantly improve outcome in cancer
involving the peritoneum
[6, 23, 26–28].
Although Gil et al. [29] showed no benefit in DSRCT and had
more toxicity with intraperitoneal cisplatin and doxorubicin, no further multiagent
chemotherapy was used in the postoperative period. Our patient was discharged
from the hospital on post-op day 7 and subsequently began cycles of adjuvant
temozolomide + irinotecan, a non-cross-resistant regimen.The combination of CHPP and
radiotherapy would be expected to result in scarring and adhesions and limit
ability to do second-look surgery. Thus
the local control option for isolated recurrent perihepatic lesions was radio frequency
ablation and cryoablation (Figure5). The use of this technique in pediatric
patients with metastatic DSRCT has been previously reported [30]. Heating increases the expression of
heat shock proteins in hepatocellular
carcinoma; these molecular chaperones are important for antigen presentation [31]. Cryoablation is a technique to not
only kill tumor cells, but avoid protein denaturation by RFA. This approach
using heat (RFA probe), then cryoablation can be considered an “in vivo
vaccine” and was first developed by S Markovic at Mayo Clinic; a clinical trial
is currently underway to study effectiveness in melanoma hepatic metastases.We found that PET-CT imaging was
useful for theevaluation of the extension of disease at presentation as well
as a useful tool for monitoring the response to therapy; therefore, we performed
PET-CT scans in our patient at every 3 months interval. The
use of PET for DSRCT has been described previously by Rosoff and Bayliff [16]. This is the first report of its use
in children after the use of continuous peritoneal perfusion and to monitor for
recurrence. Reaching a no ev-idence of
disease (NED) status and excellent quality of life was possible in our patient
with very extensive abdominopelvic DSRCT using outpatient therapy. Principles and techniques should be applicable
to other high-risk young patients with DSRCT.Finally, because inherent and
seemingly inevitable chemotherapy resistance of DSRCT, in addition to efforts
at best local control, novel therapeutic ideas are needed in the event of a relapse. The options
include new agents such as small molecule inhibitor of C-kit and PDGFR,
imatinib mesylate which has a remarkable safety profile. The current experience
of the use of imatinib in DSRCT has been recently reported by Bond et al.,
where no objective response was seen at the dose and schedule tested [32]. Other
molecules include IGF-R1 antibodies that inhibit downstream signaling of both
the mTOR and MAP kinase pathways that are important in both proliferation and
resistance to apoptosis of a variety of cancers. It is noteworthy that patients
with Ewing's family of tumors responded in
phase I trial of R1507. The SARC consortium phase II trial of R1507 opened in
early 2008 (SARC 011; sarctrials.com) and should provide a determine whether
this agent is active in DSRCT in ages 12 and up [33]. The safety profile of a multiple ascending
dose study for R1507 for children ages 2 to 17 with advanced solid tumors
(http://www.clinicaltrials.gov/)
is expected to allow participation of younger cohorts (ages 2 and up) on SARC 011 in 2008.



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