# Radiation Therapy in Addition to Gross Total Resection of Retroperitoneal Sarcoma Results in Prolonged Survival: Results from a Single Institutional Study

Authors: Timothy M. Zagar; Robert R. Shenk; Julian A. Kim; Deb Harpp; Charles A. Kunos; Fadi W. Abdul-Karim; William C. Chen; Yuji Seo; Timothy J. Kinsella
Journal: Journal of Oncology
 (2008)

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## Abstract

Purpose. Typical treatment of retroperitoneal sarcomas (RPSs) is surgery with or without radiation therapy for localized disease.  With surgery alone, local failure rates are as high as 90%; this led to radiation therapy playing an important role in the treatment of RPSs. Methods. Thirty-one patients with retroperitoneal sarcoma treated with gross total resection and radiation therapy make up this retrospective analysis. Nineteen were treated preoperatively and 12 postoperatively (median dose, 59.4 Gy)—sixteen also received intraoperative radiation therapy (IORT) (median dose, 11 Gy).  Patients were followed with stringent regimens, including frequent CT scans of the chest, abdomen, and pelvis. Results. With a median follow-up of 19 months (range 1–66 months), the 2-year overall survival (OS) rate is 70% (median, 52 months).  The 2-year locoregional control (LRC) rate is 77% (median, 61.6 months).  The 2-year distant disease free survival (DDFS) rate is 70% (median not reached).  There were no differences in radiation-related acute and late toxicities among patients treated pre- versus postoperatively, whether with or without IORT. Conclusions. Compared to surgery alone, neoadjuvant or adjuvant radiation therapy offers patients with RPS an excellent chance for long-term LRC, DDS, and OS. The integration of modern treatment planning for external beam radiation therapy and IORT allows for higher doses to be delivered with acceptable toxicities.


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## Body

## 1. Introduction

Retroperitoneal  sarcomas (RPSs) make
up  a minority of soft tissue sarcomas (STSs) diagnosed in the United States.
In 2008, it is estimated that 10 390 people will be diagnosed with an STS; of these, approximately
20%, or 2080, will occur in the retroperitoneum [1]. RPSs pose difficult diagnostic and therapeutic
problems for physicians treating them.
As a result of their location, sarcomas that arise in this area can grow
to extremely large sizes (typically >10 cm) before causing symptoms. Their large masses may encompass critical
anatomic structures, significantly decreasing the rate of complete surgical resectability
[2–4]. Only approximately half of RPSs
are surgically resectable. Without
adjuvant therapy, the risk of local recurrence ranges from 68% to more than 90%
at 10 years [5–7]. The prospect of adjuvant
radiation therapy to “sterilize” positive surgical margins and/or minimal gross
residual disease has been vital in the treatment of RPSs. Additionally, preoperative radiation therapy
is often used in an attempt to improve resectability.There has
been no published randomized trial for preoperative versus postoperative
radiation therapy in patients with RPS, as there has been for soft tissue
sarcomas of the extremity [8], largely because of the paucity of cases. As such, there is no consensus as to the
sequencing, or even the need for radiation therapy for that matter. Radiation therapy has been given in the
preoperative setting [9–12], in the hopes of converting a technically
unresectable RPS to being resectable. It
has also been given in the preoperative [13] and postoperative setting with
concurrent chemotherapy [14]. It can
also be given in the postoperative setting to help control any residual
disease, be it gross or microscopic [10, 11, 15–19]. Finally, radiation therapy can be given in
the intraoperative setting either with electrons from a linear accelerator or
with brachytherapy, both of which have been shown to increase local control [9, 10, 12, 16, 18–20].At our institution, preoperative
radiation therapy with or without intraoperative radiation therapy (IORT) has
been utilized for large, potentially difficult-to-resect RPSs. Radiation therapy is recommended in the postoperative
adjuvant setting in patients who had surgery prior to initial referral, or for
smaller RPSs that our surgeons feel they can completely resect without having
to sacrifice too much normal anatomy for the sake of achieving a gross total
resection (GTR). We report one of the
largest single institution cohorts of patients with RPS treated with modern
radiation therapy techniques, including a subset direct comparison between
those patients treated pre- versus postoperatively, to elucidate any
differences in both outcome and toxicities.


## 2. Materials and Methods

### 2.1. Patients

Between August 2000 and April 2008, 29
consecutive adult patients with a histologic diagnosis of retroperitoneal
sarcoma and 2 patients with recurrent/persistent intraabdominal aggressive fibromatosis
(desmoid tumor) were treated with at least one modality of radiation therapy at Case Medical Center in University
Hospitals. All patients were
presented to the biweekly multidisciplinary sarcoma tumor board prior to
treatment at our institution. Data were
collected retrospectively from paper charts and electronic medical records
after approval by our Cancer Center Review Board and our Institutional Review
Board.


### 2.2. Treatment Regimens

#### 2.2.1. Pre- and Postoperative External Beam Radiotherapy

Radiation therapy planning utilizing
standard computed tomography (CT)-guided 3-dimensional conformal techniques was
routinely performed, typically with 4 to 7 fields used. As the
techniques of intensity modulated (IMRT) and image-guided radiation therapy
(IGRT) utilizing TomoTherapy (Madison, Wis, USA) became available in 2004, they were utilized as
per the physician’s discretion. All
radiation treatment planning was performed by a senior radiation oncologist
(TJK).


#### 2.2.2. Intraoperative Radiation Therapy (IORT)

When clinically indicated, IORT was
administered via a Mobetron linear accelerator with electron energies of 6 to
12 MeV, prescribed to the 90% isodose line (Intraop Medical, Inc., Sunnyvale, Calif, USA).
After surgical resection of the RPS, a flat or beveled cylindrical cone
(5–10 cm) anchored
by a Bookwalter surgical clamp (Codman and Shurtleff, Inc., Raynham, Mass, USA)
was placed by both the surgeon and radiation oncologist over areas at high risk
of residual microscopic to minimal gross disease. No patients were treated with IORT for unresectable
disease. Dose-limiting normal tissues
that were in the desired IORT bed, if mobile, were physically moved out of the
field—if they were
immobile, typically 3 half value layer lead wafers were used for shielding. The technique of IORT and surgical approaches
to minimize acute and late IORT-related normal tissue toxicities are previously
detailed [21, 22].


#### 2.2.3. Surgery

A gross total resection (GTR) was
achieved when the surgeon was able to resect all areas of visible disease in
the operating room—a subtotal
resection (STR) was performed when there was any amount of gross residual
disease left behind. Anen bloc
resection of the tumor mass and expendible involved normal tissues was
attempted in all patients. Microscopic
margin status was not routinely reported, but was assumed to be positive along
soft tissue, bone, and vascular margins in the retroperitoneum.


#### 2.2.4. Follow-up

Patients were followed up by their
treating radiation oncologist after completing radiation every 3 months for the
first year, every 4 months for the 2nd year, every 6 months for the 3rd and 4th
years, then annually, with a contrast enhanced CT of the chest, abdomen, and
pelvis, and full labs with each visit.
Other ancillary studies were performed as clinically indicated.


#### 2.2.5. Normal Tissue Toxicity Analyses

Acute (1–90 days after
radiation therapy commencement) and chronic (>90 days) toxicities were
graded according to the Radiation Therapy Oncology Group (RTOG) acute and late
radiation morbidity scoring criteria [23].


#### 2.2.6. Definition of Treatment Outcomes and Statistical Considerations

The primary endpoints of this study were
locoregional control (LRC), distant disease-free survival (DDFS), and overall
survival (OS). A locoregional failure
was defined as any tumor recurrence within the abdominal/retroperitoneal
cavity, including within radiation portals.
Distant metastases (typically to liver and/or lung) were determined by
CT examinations with or without subsequent histopathologic confirmation. OS, DDFS, and LRC were calculated from the
first day of radiation therapy administration.
The patients were censored at either their last follow-up, if they
remained alive and/or disease free, or the date of their local or distant
failure or death. The Kaplan-Meier
method was used to compute LRC, DDFS, and OS [24]. Cox models were used for multivariate
analysis of prognostic factors [25]. Chi
square and Fisher’s exact tests were utilized for categorical variables and median
tests were utilized to analyze the continuous variables to compare patient groups
treated pre- versus postoperatively [26].
All measures tests were analyzed with statistical software (SPSS 12.0,
SPSS, Inc, Chicago, Ill, USA), with a 2-sided alpha level of 0.05 regarded as
statistically significant.


## 2.1. Patients

Between August 2000 and April 2008, 29
consecutive adult patients with a histologic diagnosis of retroperitoneal
sarcoma and 2 patients with recurrent/persistent intraabdominal aggressive fibromatosis
(desmoid tumor) were treated with at least one modality of radiation therapy at Case Medical Center in University
Hospitals. All patients were
presented to the biweekly multidisciplinary sarcoma tumor board prior to
treatment at our institution. Data were
collected retrospectively from paper charts and electronic medical records
after approval by our Cancer Center Review Board and our Institutional Review
Board.


## 2.2. Treatment Regimens

### 2.2.1. Pre- and Postoperative External Beam Radiotherapy

Radiation therapy planning utilizing
standard computed tomography (CT)-guided 3-dimensional conformal techniques was
routinely performed, typically with 4 to 7 fields used. As the
techniques of intensity modulated (IMRT) and image-guided radiation therapy
(IGRT) utilizing TomoTherapy (Madison, Wis, USA) became available in 2004, they were utilized as
per the physician’s discretion. All
radiation treatment planning was performed by a senior radiation oncologist
(TJK).


### 2.2.2. Intraoperative Radiation Therapy (IORT)

When clinically indicated, IORT was
administered via a Mobetron linear accelerator with electron energies of 6 to
12 MeV, prescribed to the 90% isodose line (Intraop Medical, Inc., Sunnyvale, Calif, USA).
After surgical resection of the RPS, a flat or beveled cylindrical cone
(5–10 cm) anchored
by a Bookwalter surgical clamp (Codman and Shurtleff, Inc., Raynham, Mass, USA)
was placed by both the surgeon and radiation oncologist over areas at high risk
of residual microscopic to minimal gross disease. No patients were treated with IORT for unresectable
disease. Dose-limiting normal tissues
that were in the desired IORT bed, if mobile, were physically moved out of the
field—if they were
immobile, typically 3 half value layer lead wafers were used for shielding. The technique of IORT and surgical approaches
to minimize acute and late IORT-related normal tissue toxicities are previously
detailed [21, 22].


### 2.2.3. Surgery

A gross total resection (GTR) was
achieved when the surgeon was able to resect all areas of visible disease in
the operating room—a subtotal
resection (STR) was performed when there was any amount of gross residual
disease left behind. Anen bloc
resection of the tumor mass and expendible involved normal tissues was
attempted in all patients. Microscopic
margin status was not routinely reported, but was assumed to be positive along
soft tissue, bone, and vascular margins in the retroperitoneum.


### 2.2.4. Follow-up

Patients were followed up by their
treating radiation oncologist after completing radiation every 3 months for the
first year, every 4 months for the 2nd year, every 6 months for the 3rd and 4th
years, then annually, with a contrast enhanced CT of the chest, abdomen, and
pelvis, and full labs with each visit.
Other ancillary studies were performed as clinically indicated.


### 2.2.5. Normal Tissue Toxicity Analyses

Acute (1–90 days after
radiation therapy commencement) and chronic (>90 days) toxicities were
graded according to the Radiation Therapy Oncology Group (RTOG) acute and late
radiation morbidity scoring criteria [23].


### 2.2.6. Definition of Treatment Outcomes and Statistical Considerations

The primary endpoints of this study were
locoregional control (LRC), distant disease-free survival (DDFS), and overall
survival (OS). A locoregional failure
was defined as any tumor recurrence within the abdominal/retroperitoneal
cavity, including within radiation portals.
Distant metastases (typically to liver and/or lung) were determined by
CT examinations with or without subsequent histopathologic confirmation. OS, DDFS, and LRC were calculated from the
first day of radiation therapy administration.
The patients were censored at either their last follow-up, if they
remained alive and/or disease free, or the date of their local or distant
failure or death. The Kaplan-Meier
method was used to compute LRC, DDFS, and OS [24]. Cox models were used for multivariate
analysis of prognostic factors [25]. Chi
square and Fisher’s exact tests were utilized for categorical variables and median
tests were utilized to analyze the continuous variables to compare patient groups
treated pre- versus postoperatively [26].
All measures tests were analyzed with statistical software (SPSS 12.0,
SPSS, Inc, Chicago, Ill, USA), with a 2-sided alpha level of 0.05 regarded as
statistically significant.


## 2.2.1. Pre- and Postoperative External Beam Radiotherapy

Radiation therapy planning utilizing
standard computed tomography (CT)-guided 3-dimensional conformal techniques was
routinely performed, typically with 4 to 7 fields used. As the
techniques of intensity modulated (IMRT) and image-guided radiation therapy
(IGRT) utilizing TomoTherapy (Madison, Wis, USA) became available in 2004, they were utilized as
per the physician’s discretion. All
radiation treatment planning was performed by a senior radiation oncologist
(TJK).


## 2.2.2. Intraoperative Radiation Therapy (IORT)

When clinically indicated, IORT was
administered via a Mobetron linear accelerator with electron energies of 6 to
12 MeV, prescribed to the 90% isodose line (Intraop Medical, Inc., Sunnyvale, Calif, USA).
After surgical resection of the RPS, a flat or beveled cylindrical cone
(5–10 cm) anchored
by a Bookwalter surgical clamp (Codman and Shurtleff, Inc., Raynham, Mass, USA)
was placed by both the surgeon and radiation oncologist over areas at high risk
of residual microscopic to minimal gross disease. No patients were treated with IORT for unresectable
disease. Dose-limiting normal tissues
that were in the desired IORT bed, if mobile, were physically moved out of the
field—if they were
immobile, typically 3 half value layer lead wafers were used for shielding. The technique of IORT and surgical approaches
to minimize acute and late IORT-related normal tissue toxicities are previously
detailed [21, 22].


## 2.2.3. Surgery

A gross total resection (GTR) was
achieved when the surgeon was able to resect all areas of visible disease in
the operating room—a subtotal
resection (STR) was performed when there was any amount of gross residual
disease left behind. Anen bloc
resection of the tumor mass and expendible involved normal tissues was
attempted in all patients. Microscopic
margin status was not routinely reported, but was assumed to be positive along
soft tissue, bone, and vascular margins in the retroperitoneum.


## 2.2.4. Follow-up

Patients were followed up by their
treating radiation oncologist after completing radiation every 3 months for the
first year, every 4 months for the 2nd year, every 6 months for the 3rd and 4th
years, then annually, with a contrast enhanced CT of the chest, abdomen, and
pelvis, and full labs with each visit.
Other ancillary studies were performed as clinically indicated.


## 2.2.5. Normal Tissue Toxicity Analyses

Acute (1–90 days after
radiation therapy commencement) and chronic (>90 days) toxicities were
graded according to the Radiation Therapy Oncology Group (RTOG) acute and late
radiation morbidity scoring criteria [23].


## 2.2.6. Definition of Treatment Outcomes and Statistical Considerations

The primary endpoints of this study were
locoregional control (LRC), distant disease-free survival (DDFS), and overall
survival (OS). A locoregional failure
was defined as any tumor recurrence within the abdominal/retroperitoneal
cavity, including within radiation portals.
Distant metastases (typically to liver and/or lung) were determined by
CT examinations with or without subsequent histopathologic confirmation. OS, DDFS, and LRC were calculated from the
first day of radiation therapy administration.
The patients were censored at either their last follow-up, if they
remained alive and/or disease free, or the date of their local or distant
failure or death. The Kaplan-Meier
method was used to compute LRC, DDFS, and OS [24]. Cox models were used for multivariate
analysis of prognostic factors [25]. Chi
square and Fisher’s exact tests were utilized for categorical variables and median
tests were utilized to analyze the continuous variables to compare patient groups
treated pre- versus postoperatively [26].
All measures tests were analyzed with statistical software (SPSS 12.0,
SPSS, Inc, Chicago, Ill, USA), with a 2-sided alpha level of 0.05 regarded as
statistically significant.


## 3. Results

### 3.1. Patient and Treatment Characteristics

Twenty-nine consecutive patients with
biopsy proven retroperitoneal sarcoma and 2 patients with intraabdominal
fibromatosis (desmoid tumor) were treated and closely followed over this 8+
year period, for a median of 19 months (range 1–66 months). The 2 patients with large intraabdominal
desmoid tumors were included in this analysis due to the highly aggressive
nature of their lesions—in fact, one
patient had positive lymph nodes at the time of surgical resection. Females made up the majority (65%) of
patients, and Caucasians accounted for the overwhelming majority (90%). Most frequently, patients presented with
either pain or some type of vague abdominal discomfort, or unintentional weight
loss (Table1). Overall, 26 (84%) patients
were able to have a gross total resection of their RPSs; 15 (79%) of the
patients were treated preoperatively and 11 (92%) of the patients were treated
postoperatively. Patients treated
postoperatively generally had smaller tumors (≤10 cm) at presentation. When separated into sequencing of treatment, 19
(61%) patients were treated preoperatively (median dose 59.4 Gy, range 36.8–63.4 Gy), with
the goal of improving the likelihood of achieving gross total resection; one
patient was palliated for her SVC syndrome, which was her presenting symptom. Twelve (39%) patients were treated in the
postoperative setting (median 59.4 Gy, range 54–68.4 Gy) (Table 2). Both groups were well matched with respect to
patient characteristics, pathology, grade, clinical stage, histology, and
extent of surgical resection. However, the
only statistically significant difference between the groups was the use of
IORT and IMRT. Thirteen (68%) patients were
treated with preoperative EBRT received IORT, compared to only 3 (25%) patients
who received IORT followed by postoperative EBRT, based on the recommendations
of the multidisciplinary sarcoma tumor board (P=.03, Table 2). Eight (67%) patients treated with
postoperative EBRT were treated with IMRT/IGRT versus only 2 (11%) patients in
the preoperative group, based on the availability of TomoTherapy (P=.003).Table 1
Patient and tumor characteristics (all
patients).
ParameterNo. of patients (%)SexMale11 (35%)Female20 (65%)Age (range)56 (20–83)RaceCaucasian28 (90%)African American3 (10%)History of tobacco use11 (35%)Family history of malignancy7 (23%)Breast cancer4 (13%)Breast and ovarian cancers2 (6%)Sarcoma1 (3%)Prior cancer4 (13%)Breast1 (3%)Melanoma1 (3%)Hodgkin’s disease1 (3%)Prior radiation3 (10%)TNM stageT2bN0M025 (81%)T2bN0M14 (13%)Desmoid2 (6%)Grade16 (19%)26 (19%)317 (55%)AJCC stageI10 (32%)III15 (48%)IV4 (13%)Recurrent RPS7 (23%)Pretreatment size of RPS (range)10.5 cm (4.0–20.0)HistologyLeiomyosarcoma15 (48%)Liposarcoma10 (32%)Myxoid3 (10%)Dedifferentiated4 (13%)Desmoid2 (6%)Malignant fibrous histiocytoma3 (10%)Inflammatory myofibroblastic sarcoma1 (3%)CD 117 stainingNot done16 (52%)Negative10 (32%)Positive5 (16%)Imatinib mesylate given1 (3%)Symptoms at presentationPain/discomfort20 (65%)Weight loss (range)9 (31%) 10–30 lbsEarly satiety/decreased appetite6 (21%)Nausea3 (10%)Change in menses2 (7%)Small bowel obstruction2 (7%)Table 2
Patient, tumor, and treatment characteristics.
ParametersPreoperative EBRT group(n=19)Postoperative EBRT group(n=12)P   valueGenderFemale12 (63%)8 (67%)1.00Male7 (37%)4 (33%)Age at presentation≤50 years8 (42%)2 (17%).24>50 years11 (58%)10 (83%)AJCC stageI5 (26%)5 (42%).24III12 (63%)3 (25%)IV2 (11%)2 (17%)Grade13 (16%)3 (25%).6624 (21%)2 (17%)312 (63%)5 (42%)Tumor size≤10 cm7 (37%)9 (75%).07>10 cm12 (63%)3 (25%)Lesion presentationPrimary17 (89%)7 (58%).08Recurrent2 (11%)5 (42%)HistologyLeiomyosarcoma9 (47%)6 (50%).72Liposarcoma7 (37%)3 (25%)Other3 (16%)3 (25%)Extent resectionSTR4 (21%)1 (8%).62GTR15 (79%)11 (92%)Organs removedNo9 (47%)3 (25%).27Yes10 (53%)9 (75%)ChemoNo16 (84%)9 (75%).65Yes3 (16%)3 (25%)IORTNo6 (32%)9 (75%).03Yes (1 pt each arm
had 2 fields)13 (68%)3 (25%)Radiotherapy doseEBRT median (range)59.4 Gy (36.8–63.4 Gy)59.4 Gy (54–68.4).79IORT median (range)11 Gy (10–12 Gy)11 Gy (10–12 Gy)IMRTNo17 (89%)4 (33%).002Yes2 (11%)8 (67%)Time to complete EBRT
Median (range)45 days
(17–90 days)44 days
(41–55 days).76Length of F/U
Median (range)22 months
(0.6–56.5 months)13.05 months
(1.4–66.4 months).55EBRT = external beam radiation therapy; STR = subtotal resection; GTR = gross total
resection; IORT = intraoperative radiation therapy; IMRT = intensity modulated
radiation therapy; F/U = follow-up.


#### 3.1.1. Locoregional Control

Overall, the 31 patients have a
median locoregional control rate (LRC) of 61.6 months, with a 2-year LRC rate of
77%(SE+/−18%) (Figure 1(a)). Two
patients in the preoperative group and 1 patient in the postoperative group
developed a locoregional failure as their first site of failure. There was no statistically significant
difference in LRC rates in patients treated pre- versus postoperatively (P=.79) (Figure 1(b)). The use of IORT
did not have an impact on LRC (P=.550) (Table 3).Table 3
Cox regression
multivariate analysis when controlled for pre- versus postoperative treatment.
Locoregional controlDistant disease free survivalOverall survivalAgeP = .98P = .79P = .81GenderP = .76P = .12P = .72StageP = .95P = .21P = .99GradeP = .81P = .57P = .93Tumor sizeP = .76P = .46P = .96Primary versus recurrentP = .60P = .27P = .65HistologyP = .70P = .53P = .92GTR/STRP = .55P = .41P = .77IORTP = .55P = .42P = .76ChemoP = .83P = .39P = .77EBRT doseP = .79P = .28P = .60Organ resectedP = .85P = .34P = .66GTR = gross total resection; STR = subtotal resection; IORT = intraoperative
radiation therapy; EBRT = external beam radiation therapy.(a) Locoregional control: all 31 patients. (b)
Locoregional control: pre- versus postoperative EBRT(P=.79). EBRT =
external beam radiation therapy.
(a)(b)


#### 3.1.2. Distant Metastases

The median distant disease-free
survival (DDFS) has not yet been achieved, with a 2-year DDFS of 70%(SE+/−18%)
(Figure 2(a)). All 7 patients who developed
metastatic disease did so within the first 14 months of beginning radiation
therapy (median 4.8 months, range 4.2–14.2 months). Treatment for metastases was physician
dependent—all were offered
chemotherapy. One patient underwent
multiple video-assisted thorascopic (VATS) resections of his pulmonary
metastases, while one other received palliative radiation therapy to her lung
metastases. Four patients in the
preoperative group and 2 patients in the postoperative group developed distant
metastases as their first site of failure—two patients in
the postoperative group developed synchronous distant and locoregional
failures. There was no statistically
significant difference in DDFS rates in patients treated pre- versus
postoperatively (P=.73), whether with or without IORT (P=.42); see Figure 2(b)
and Table 3.(a) Distant disease free survival: all 31
patients. (b) Distant disease free survival: pre- versus postoperative EBRT(P=.73). EBRT = external beam radiation therapy.
(a)(b)


#### 3.2. Overall Survival

The median overall survival for this
patient cohort was 52 months, with a 2-year OS rate of 70%(SE+/−19%) (Figure 3(a)). Nine patients died during
follow-up, with 8 of these directly attributable to retroperitoneal sarcoma. The other death occurred in a patient who
suffered from a complicated postoperative course, including intractable
clostridium difficile colitis. At last
follow-up (5.8 months), she was free of both local and recurrent disease, but she
was ultimately lost to follow-up. There
was no statistically significant difference in DDFS rates in patients treated
pre- versus postoperatively (P=.14), whether with or without IORT (P=.77); see Figure 3(b) and Table 3.(a) Overall survival: all 31 patients. (b) Overall survival: pre- versus
postoperative EBRT(P=.14). EBRT = external beam radiation therapy.
(a)(b)


### 3.3. Prognostic Factors for LRC, DDFS, and OS

There were two trends that approached statistical significance; those patients treated postoperatively had a trend to have lesions≤10 cm (P=.07), and were more likely to present with recurrent disease (P=.08). In our cohort of patients, after controlling for whether patients were treated in the preoperative or postoperative setting, none of the commonly cited
characteristics had a statistically significant impact on LRC, DDFS, or OS, on multivariate analysis (Table 3).


#### 3.3.1. Toxicity

Most patients (90%) completed the
planned course of radiation therapy without significant (≥grade 3) acute
effects. Acute and late toxicities were similar
between the pre- and postoperative groups (Table4). There were 3 grade 3-4 acute radiation-related
toxicities (all 3 in the preoperative group), and 17 grade 3-4 late toxicities
(11 in the preoperative group, 6 in the postoperative group)—no grade 5 treatment-related
toxicities occurred. The most common acute side effect seen, with
almost 90% of patients overall experiencing, was grade 1-2 gastrointestinal
complaints, most commonly being nausea and/or diarrhea. These grade 1-2 toxicities responded to
conservative medical treatment. Late
toxicities occurred less frequently and there were no statistically significant
differences in late grade 3-4 toxicities between those patients treated pre-
versus postoperatively (Table 4). Once
again, late GI toxicities were the most common type of a late side effect—when they
occurred, they were more often grade 3 to 4, including requiring emergency
surgery for small bowel obstruction related to adhesions (one patient each in
the preoperative and postoperative groups).
There was one grade 1 (asymptomatic) jejunal stricture found at surgery
for another reason, in a patient treated postoperatively, that was presumed to
be radiation-related. One patient who
was treated with postoperative radiation therapy for his second locoregional
failure, and then preoperatively for his third locoregional failure, suffered
from chronic small bowel obstructions.
The only fistula that was documented in our series occurred in a patient
who had 5 metachronous locoregional failures, and who was radiated preoperatively
with gross total resection of her fourth and later fifth locoregional failures.Table 4
RTOG acute and late toxicities of radiation.
ParametersPreoperative EBRT group(n=19)Postoperative EBRT group(n=12)P valueAcute (≤90 days)GIGrade 1-216 (84%)11 (92%).70Grade 3-41 (5%)0 (0%)GUGrade 1-20 (0%)3 (25%).05Grade 3-40 (0%)0 (0%)Wound complicationsGrade 1-20 (0%)1 (8%).39Grade 3-40 (0%)0 (0%)InfectionGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)SkinGrade 1-22 (11%)1 (8%)1.00Grade 3-40 (0%)0 (0%)PainGrade 1-211 (58%)5 (42%).47Grade 3-40 (0%)0 (0%)NeurologicGrade 1-22 (11%)0 (0%).51Grade 3-40 (0%)0 (0%)GynecologicGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)Late (>90 days)GIGrade 1-21 (5%)2 (17%).51Grade 3-43 (16%)3 (25%)GUGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)Wound complicationsGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)InfectionGrade 1-20 (0%)0 (0%).31Grade 3-44 (21%)2 (17%)SkinGrade 1-20 (0%)0 (0%)NSGrade 3-40 (0%)0 (0%)PainGrade 1-21 (5%)0 (0%)1.00Grade 3-40 (0%)0 (0%)NeurologicGrade 1-21 (5%)0 (0%)1.00Grade 3-40 (0%)0 (0%)GynecologicGrade 1-20 (0%)0 (0%)1.00Grade 3-42 (11%)1 (8%)LymphedemaGrade 1-21 (5%)0 (0%)1.00Grade 3-40 (0%)0 (0%)RTOG = Radiation therapy oncology
group; EBRT = external beam radiation therapy; GI = gastrointestinal; GU =
genitourinary.A total of 16 patients reported grade
1-2 pain or abdominal discomfort during radiation therapy—11 in the
preoperative group and 5 in the postoperative group(P=.47). As these tumors are often symptomatic with
pain at presentation, a multifactorial cause of the pain/discomfort was
likely. Narcotics were used judiciously
in these patients. Those patients
treated postoperatively had more frequent acute grade 1-2 genitourinary-related
toxicities, when compared to the preoperative cohort (P=.05). There was no statistically significant
difference in wound healing and/or infection in the two different cohorts—3 patients in the
preoperative group and 1 patient treated postoperatively developed abscesses
more than 90 days after radiation that required drainage (P=.31). Radiation-induced menopause was seen in 3
patients—2 treated
preoperatively, and one in the postoperative setting.


## 3.1. Patient and Treatment Characteristics

Twenty-nine consecutive patients with
biopsy proven retroperitoneal sarcoma and 2 patients with intraabdominal
fibromatosis (desmoid tumor) were treated and closely followed over this 8+
year period, for a median of 19 months (range 1–66 months). The 2 patients with large intraabdominal
desmoid tumors were included in this analysis due to the highly aggressive
nature of their lesions—in fact, one
patient had positive lymph nodes at the time of surgical resection. Females made up the majority (65%) of
patients, and Caucasians accounted for the overwhelming majority (90%). Most frequently, patients presented with
either pain or some type of vague abdominal discomfort, or unintentional weight
loss (Table1). Overall, 26 (84%) patients
were able to have a gross total resection of their RPSs; 15 (79%) of the
patients were treated preoperatively and 11 (92%) of the patients were treated
postoperatively. Patients treated
postoperatively generally had smaller tumors (≤10 cm) at presentation. When separated into sequencing of treatment, 19
(61%) patients were treated preoperatively (median dose 59.4 Gy, range 36.8–63.4 Gy), with
the goal of improving the likelihood of achieving gross total resection; one
patient was palliated for her SVC syndrome, which was her presenting symptom. Twelve (39%) patients were treated in the
postoperative setting (median 59.4 Gy, range 54–68.4 Gy) (Table 2). Both groups were well matched with respect to
patient characteristics, pathology, grade, clinical stage, histology, and
extent of surgical resection. However, the
only statistically significant difference between the groups was the use of
IORT and IMRT. Thirteen (68%) patients were
treated with preoperative EBRT received IORT, compared to only 3 (25%) patients
who received IORT followed by postoperative EBRT, based on the recommendations
of the multidisciplinary sarcoma tumor board (P=.03, Table 2). Eight (67%) patients treated with
postoperative EBRT were treated with IMRT/IGRT versus only 2 (11%) patients in
the preoperative group, based on the availability of TomoTherapy (P=.003).Table 1
Patient and tumor characteristics (all
patients).
ParameterNo. of patients (%)SexMale11 (35%)Female20 (65%)Age (range)56 (20–83)RaceCaucasian28 (90%)African American3 (10%)History of tobacco use11 (35%)Family history of malignancy7 (23%)Breast cancer4 (13%)Breast and ovarian cancers2 (6%)Sarcoma1 (3%)Prior cancer4 (13%)Breast1 (3%)Melanoma1 (3%)Hodgkin’s disease1 (3%)Prior radiation3 (10%)TNM stageT2bN0M025 (81%)T2bN0M14 (13%)Desmoid2 (6%)Grade16 (19%)26 (19%)317 (55%)AJCC stageI10 (32%)III15 (48%)IV4 (13%)Recurrent RPS7 (23%)Pretreatment size of RPS (range)10.5 cm (4.0–20.0)HistologyLeiomyosarcoma15 (48%)Liposarcoma10 (32%)Myxoid3 (10%)Dedifferentiated4 (13%)Desmoid2 (6%)Malignant fibrous histiocytoma3 (10%)Inflammatory myofibroblastic sarcoma1 (3%)CD 117 stainingNot done16 (52%)Negative10 (32%)Positive5 (16%)Imatinib mesylate given1 (3%)Symptoms at presentationPain/discomfort20 (65%)Weight loss (range)9 (31%) 10–30 lbsEarly satiety/decreased appetite6 (21%)Nausea3 (10%)Change in menses2 (7%)Small bowel obstruction2 (7%)Table 2
Patient, tumor, and treatment characteristics.
ParametersPreoperative EBRT group(n=19)Postoperative EBRT group(n=12)P   valueGenderFemale12 (63%)8 (67%)1.00Male7 (37%)4 (33%)Age at presentation≤50 years8 (42%)2 (17%).24>50 years11 (58%)10 (83%)AJCC stageI5 (26%)5 (42%).24III12 (63%)3 (25%)IV2 (11%)2 (17%)Grade13 (16%)3 (25%).6624 (21%)2 (17%)312 (63%)5 (42%)Tumor size≤10 cm7 (37%)9 (75%).07>10 cm12 (63%)3 (25%)Lesion presentationPrimary17 (89%)7 (58%).08Recurrent2 (11%)5 (42%)HistologyLeiomyosarcoma9 (47%)6 (50%).72Liposarcoma7 (37%)3 (25%)Other3 (16%)3 (25%)Extent resectionSTR4 (21%)1 (8%).62GTR15 (79%)11 (92%)Organs removedNo9 (47%)3 (25%).27Yes10 (53%)9 (75%)ChemoNo16 (84%)9 (75%).65Yes3 (16%)3 (25%)IORTNo6 (32%)9 (75%).03Yes (1 pt each arm
had 2 fields)13 (68%)3 (25%)Radiotherapy doseEBRT median (range)59.4 Gy (36.8–63.4 Gy)59.4 Gy (54–68.4).79IORT median (range)11 Gy (10–12 Gy)11 Gy (10–12 Gy)IMRTNo17 (89%)4 (33%).002Yes2 (11%)8 (67%)Time to complete EBRT
Median (range)45 days
(17–90 days)44 days
(41–55 days).76Length of F/U
Median (range)22 months
(0.6–56.5 months)13.05 months
(1.4–66.4 months).55EBRT = external beam radiation therapy; STR = subtotal resection; GTR = gross total
resection; IORT = intraoperative radiation therapy; IMRT = intensity modulated
radiation therapy; F/U = follow-up.


### 3.1.1. Locoregional Control

Overall, the 31 patients have a
median locoregional control rate (LRC) of 61.6 months, with a 2-year LRC rate of
77%(SE+/−18%) (Figure 1(a)). Two
patients in the preoperative group and 1 patient in the postoperative group
developed a locoregional failure as their first site of failure. There was no statistically significant
difference in LRC rates in patients treated pre- versus postoperatively (P=.79) (Figure 1(b)). The use of IORT
did not have an impact on LRC (P=.550) (Table 3).Table 3
Cox regression
multivariate analysis when controlled for pre- versus postoperative treatment.
Locoregional controlDistant disease free survivalOverall survivalAgeP = .98P = .79P = .81GenderP = .76P = .12P = .72StageP = .95P = .21P = .99GradeP = .81P = .57P = .93Tumor sizeP = .76P = .46P = .96Primary versus recurrentP = .60P = .27P = .65HistologyP = .70P = .53P = .92GTR/STRP = .55P = .41P = .77IORTP = .55P = .42P = .76ChemoP = .83P = .39P = .77EBRT doseP = .79P = .28P = .60Organ resectedP = .85P = .34P = .66GTR = gross total resection; STR = subtotal resection; IORT = intraoperative
radiation therapy; EBRT = external beam radiation therapy.(a) Locoregional control: all 31 patients. (b)
Locoregional control: pre- versus postoperative EBRT(P=.79). EBRT =
external beam radiation therapy.
(a)(b)


### 3.1.2. Distant Metastases

The median distant disease-free
survival (DDFS) has not yet been achieved, with a 2-year DDFS of 70%(SE+/−18%)
(Figure 2(a)). All 7 patients who developed
metastatic disease did so within the first 14 months of beginning radiation
therapy (median 4.8 months, range 4.2–14.2 months). Treatment for metastases was physician
dependent—all were offered
chemotherapy. One patient underwent
multiple video-assisted thorascopic (VATS) resections of his pulmonary
metastases, while one other received palliative radiation therapy to her lung
metastases. Four patients in the
preoperative group and 2 patients in the postoperative group developed distant
metastases as their first site of failure—two patients in
the postoperative group developed synchronous distant and locoregional
failures. There was no statistically
significant difference in DDFS rates in patients treated pre- versus
postoperatively (P=.73), whether with or without IORT (P=.42); see Figure 2(b)
and Table 3.(a) Distant disease free survival: all 31
patients. (b) Distant disease free survival: pre- versus postoperative EBRT(P=.73). EBRT = external beam radiation therapy.
(a)(b)


### 3.2. Overall Survival

The median overall survival for this
patient cohort was 52 months, with a 2-year OS rate of 70%(SE+/−19%) (Figure 3(a)). Nine patients died during
follow-up, with 8 of these directly attributable to retroperitoneal sarcoma. The other death occurred in a patient who
suffered from a complicated postoperative course, including intractable
clostridium difficile colitis. At last
follow-up (5.8 months), she was free of both local and recurrent disease, but she
was ultimately lost to follow-up. There
was no statistically significant difference in DDFS rates in patients treated
pre- versus postoperatively (P=.14), whether with or without IORT (P=.77); see Figure 3(b) and Table 3.(a) Overall survival: all 31 patients. (b) Overall survival: pre- versus
postoperative EBRT(P=.14). EBRT = external beam radiation therapy.
(a)(b)


## 3.1.1. Locoregional Control

Overall, the 31 patients have a
median locoregional control rate (LRC) of 61.6 months, with a 2-year LRC rate of
77%(SE+/−18%) (Figure 1(a)). Two
patients in the preoperative group and 1 patient in the postoperative group
developed a locoregional failure as their first site of failure. There was no statistically significant
difference in LRC rates in patients treated pre- versus postoperatively (P=.79) (Figure 1(b)). The use of IORT
did not have an impact on LRC (P=.550) (Table 3).Table 3
Cox regression
multivariate analysis when controlled for pre- versus postoperative treatment.
Locoregional controlDistant disease free survivalOverall survivalAgeP = .98P = .79P = .81GenderP = .76P = .12P = .72StageP = .95P = .21P = .99GradeP = .81P = .57P = .93Tumor sizeP = .76P = .46P = .96Primary versus recurrentP = .60P = .27P = .65HistologyP = .70P = .53P = .92GTR/STRP = .55P = .41P = .77IORTP = .55P = .42P = .76ChemoP = .83P = .39P = .77EBRT doseP = .79P = .28P = .60Organ resectedP = .85P = .34P = .66GTR = gross total resection; STR = subtotal resection; IORT = intraoperative
radiation therapy; EBRT = external beam radiation therapy.(a) Locoregional control: all 31 patients. (b)
Locoregional control: pre- versus postoperative EBRT(P=.79). EBRT =
external beam radiation therapy.
(a)(b)


## 3.1.2. Distant Metastases

The median distant disease-free
survival (DDFS) has not yet been achieved, with a 2-year DDFS of 70%(SE+/−18%)
(Figure 2(a)). All 7 patients who developed
metastatic disease did so within the first 14 months of beginning radiation
therapy (median 4.8 months, range 4.2–14.2 months). Treatment for metastases was physician
dependent—all were offered
chemotherapy. One patient underwent
multiple video-assisted thorascopic (VATS) resections of his pulmonary
metastases, while one other received palliative radiation therapy to her lung
metastases. Four patients in the
preoperative group and 2 patients in the postoperative group developed distant
metastases as their first site of failure—two patients in
the postoperative group developed synchronous distant and locoregional
failures. There was no statistically
significant difference in DDFS rates in patients treated pre- versus
postoperatively (P=.73), whether with or without IORT (P=.42); see Figure 2(b)
and Table 3.(a) Distant disease free survival: all 31
patients. (b) Distant disease free survival: pre- versus postoperative EBRT(P=.73). EBRT = external beam radiation therapy.
(a)(b)


## 3.2. Overall Survival

The median overall survival for this
patient cohort was 52 months, with a 2-year OS rate of 70%(SE+/−19%) (Figure 3(a)). Nine patients died during
follow-up, with 8 of these directly attributable to retroperitoneal sarcoma. The other death occurred in a patient who
suffered from a complicated postoperative course, including intractable
clostridium difficile colitis. At last
follow-up (5.8 months), she was free of both local and recurrent disease, but she
was ultimately lost to follow-up. There
was no statistically significant difference in DDFS rates in patients treated
pre- versus postoperatively (P=.14), whether with or without IORT (P=.77); see Figure 3(b) and Table 3.(a) Overall survival: all 31 patients. (b) Overall survival: pre- versus
postoperative EBRT(P=.14). EBRT = external beam radiation therapy.
(a)(b)


## 3.3. Prognostic Factors for LRC, DDFS, and OS

There were two trends that approached statistical significance; those patients treated postoperatively had a trend to have lesions≤10 cm (P=.07), and were more likely to present with recurrent disease (P=.08). In our cohort of patients, after controlling for whether patients were treated in the preoperative or postoperative setting, none of the commonly cited
characteristics had a statistically significant impact on LRC, DDFS, or OS, on multivariate analysis (Table 3).


### 3.3.1. Toxicity

Most patients (90%) completed the
planned course of radiation therapy without significant (≥grade 3) acute
effects. Acute and late toxicities were similar
between the pre- and postoperative groups (Table4). There were 3 grade 3-4 acute radiation-related
toxicities (all 3 in the preoperative group), and 17 grade 3-4 late toxicities
(11 in the preoperative group, 6 in the postoperative group)—no grade 5 treatment-related
toxicities occurred. The most common acute side effect seen, with
almost 90% of patients overall experiencing, was grade 1-2 gastrointestinal
complaints, most commonly being nausea and/or diarrhea. These grade 1-2 toxicities responded to
conservative medical treatment. Late
toxicities occurred less frequently and there were no statistically significant
differences in late grade 3-4 toxicities between those patients treated pre-
versus postoperatively (Table 4). Once
again, late GI toxicities were the most common type of a late side effect—when they
occurred, they were more often grade 3 to 4, including requiring emergency
surgery for small bowel obstruction related to adhesions (one patient each in
the preoperative and postoperative groups).
There was one grade 1 (asymptomatic) jejunal stricture found at surgery
for another reason, in a patient treated postoperatively, that was presumed to
be radiation-related. One patient who
was treated with postoperative radiation therapy for his second locoregional
failure, and then preoperatively for his third locoregional failure, suffered
from chronic small bowel obstructions.
The only fistula that was documented in our series occurred in a patient
who had 5 metachronous locoregional failures, and who was radiated preoperatively
with gross total resection of her fourth and later fifth locoregional failures.Table 4
RTOG acute and late toxicities of radiation.
ParametersPreoperative EBRT group(n=19)Postoperative EBRT group(n=12)P valueAcute (≤90 days)GIGrade 1-216 (84%)11 (92%).70Grade 3-41 (5%)0 (0%)GUGrade 1-20 (0%)3 (25%).05Grade 3-40 (0%)0 (0%)Wound complicationsGrade 1-20 (0%)1 (8%).39Grade 3-40 (0%)0 (0%)InfectionGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)SkinGrade 1-22 (11%)1 (8%)1.00Grade 3-40 (0%)0 (0%)PainGrade 1-211 (58%)5 (42%).47Grade 3-40 (0%)0 (0%)NeurologicGrade 1-22 (11%)0 (0%).51Grade 3-40 (0%)0 (0%)GynecologicGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)Late (>90 days)GIGrade 1-21 (5%)2 (17%).51Grade 3-43 (16%)3 (25%)GUGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)Wound complicationsGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)InfectionGrade 1-20 (0%)0 (0%).31Grade 3-44 (21%)2 (17%)SkinGrade 1-20 (0%)0 (0%)NSGrade 3-40 (0%)0 (0%)PainGrade 1-21 (5%)0 (0%)1.00Grade 3-40 (0%)0 (0%)NeurologicGrade 1-21 (5%)0 (0%)1.00Grade 3-40 (0%)0 (0%)GynecologicGrade 1-20 (0%)0 (0%)1.00Grade 3-42 (11%)1 (8%)LymphedemaGrade 1-21 (5%)0 (0%)1.00Grade 3-40 (0%)0 (0%)RTOG = Radiation therapy oncology
group; EBRT = external beam radiation therapy; GI = gastrointestinal; GU =
genitourinary.A total of 16 patients reported grade
1-2 pain or abdominal discomfort during radiation therapy—11 in the
preoperative group and 5 in the postoperative group(P=.47). As these tumors are often symptomatic with
pain at presentation, a multifactorial cause of the pain/discomfort was
likely. Narcotics were used judiciously
in these patients. Those patients
treated postoperatively had more frequent acute grade 1-2 genitourinary-related
toxicities, when compared to the preoperative cohort (P=.05). There was no statistically significant
difference in wound healing and/or infection in the two different cohorts—3 patients in the
preoperative group and 1 patient treated postoperatively developed abscesses
more than 90 days after radiation that required drainage (P=.31). Radiation-induced menopause was seen in 3
patients—2 treated
preoperatively, and one in the postoperative setting.


## 3.3.1. Toxicity

Most patients (90%) completed the
planned course of radiation therapy without significant (≥grade 3) acute
effects. Acute and late toxicities were similar
between the pre- and postoperative groups (Table4). There were 3 grade 3-4 acute radiation-related
toxicities (all 3 in the preoperative group), and 17 grade 3-4 late toxicities
(11 in the preoperative group, 6 in the postoperative group)—no grade 5 treatment-related
toxicities occurred. The most common acute side effect seen, with
almost 90% of patients overall experiencing, was grade 1-2 gastrointestinal
complaints, most commonly being nausea and/or diarrhea. These grade 1-2 toxicities responded to
conservative medical treatment. Late
toxicities occurred less frequently and there were no statistically significant
differences in late grade 3-4 toxicities between those patients treated pre-
versus postoperatively (Table 4). Once
again, late GI toxicities were the most common type of a late side effect—when they
occurred, they were more often grade 3 to 4, including requiring emergency
surgery for small bowel obstruction related to adhesions (one patient each in
the preoperative and postoperative groups).
There was one grade 1 (asymptomatic) jejunal stricture found at surgery
for another reason, in a patient treated postoperatively, that was presumed to
be radiation-related. One patient who
was treated with postoperative radiation therapy for his second locoregional
failure, and then preoperatively for his third locoregional failure, suffered
from chronic small bowel obstructions.
The only fistula that was documented in our series occurred in a patient
who had 5 metachronous locoregional failures, and who was radiated preoperatively
with gross total resection of her fourth and later fifth locoregional failures.Table 4
RTOG acute and late toxicities of radiation.
ParametersPreoperative EBRT group(n=19)Postoperative EBRT group(n=12)P valueAcute (≤90 days)GIGrade 1-216 (84%)11 (92%).70Grade 3-41 (5%)0 (0%)GUGrade 1-20 (0%)3 (25%).05Grade 3-40 (0%)0 (0%)Wound complicationsGrade 1-20 (0%)1 (8%).39Grade 3-40 (0%)0 (0%)InfectionGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)SkinGrade 1-22 (11%)1 (8%)1.00Grade 3-40 (0%)0 (0%)PainGrade 1-211 (58%)5 (42%).47Grade 3-40 (0%)0 (0%)NeurologicGrade 1-22 (11%)0 (0%).51Grade 3-40 (0%)0 (0%)GynecologicGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)Late (>90 days)GIGrade 1-21 (5%)2 (17%).51Grade 3-43 (16%)3 (25%)GUGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)Wound complicationsGrade 1-20 (0%)0 (0%)1.00Grade 3-41 (5%)0 (0%)InfectionGrade 1-20 (0%)0 (0%).31Grade 3-44 (21%)2 (17%)SkinGrade 1-20 (0%)0 (0%)NSGrade 3-40 (0%)0 (0%)PainGrade 1-21 (5%)0 (0%)1.00Grade 3-40 (0%)0 (0%)NeurologicGrade 1-21 (5%)0 (0%)1.00Grade 3-40 (0%)0 (0%)GynecologicGrade 1-20 (0%)0 (0%)1.00Grade 3-42 (11%)1 (8%)LymphedemaGrade 1-21 (5%)0 (0%)1.00Grade 3-40 (0%)0 (0%)RTOG = Radiation therapy oncology
group; EBRT = external beam radiation therapy; GI = gastrointestinal; GU =
genitourinary.A total of 16 patients reported grade
1-2 pain or abdominal discomfort during radiation therapy—11 in the
preoperative group and 5 in the postoperative group(P=.47). As these tumors are often symptomatic with
pain at presentation, a multifactorial cause of the pain/discomfort was
likely. Narcotics were used judiciously
in these patients. Those patients
treated postoperatively had more frequent acute grade 1-2 genitourinary-related
toxicities, when compared to the preoperative cohort (P=.05). There was no statistically significant
difference in wound healing and/or infection in the two different cohorts—3 patients in the
preoperative group and 1 patient treated postoperatively developed abscesses
more than 90 days after radiation that required drainage (P=.31). Radiation-induced menopause was seen in 3
patients—2 treated
preoperatively, and one in the postoperative setting.


## 4. Discussion

Feng et al. reported on a large group of
85 patients with RPS radiated over a 20-year period [11]. Their 2-year LC, DDFS, and OS rates were 66%,
62%, and 70%, compared to our 77%, 70%, and 70%, respectively. They were the first to report an apparent
dose response relationship with adjuvant radiation therapy for RPS, with higher
doses (≥55.8 Gy) being associated with improved LC, but with no effect on
overall survival [11]. Typically, doses of 45 Gy to 50.4 Gy have been
utilized in the preoperative setting for RPSs [9, 10, 12, 13]. Our 2-year rate of LRC may be, in fact, due
to the higher doses of radiation used (median dose, 59.4 Gy) which may have an
impact on DDFS. We routinely used this
higher dose in the preoperative setting, as we have extrapolated from our own
institution’s data for extremity soft tissue sarcomas, with all patients—both those
treated pre- and postoperatively—receiving a
median dose of 59.4 Gy [27].A direct comparison of treatment
outcomes following combined surgery and radiation therapy for patients with
retroperitoneal sarcomas is particularly difficult as there is no standardized
definition of what is a local failure. Some
reports, like our study, define a local failure as any recurrence of disease in
the abdominal cavity, save the hepatic parenchyma [9]. Other reports use more stringent definitions and divide locoregional failure
into “central” (within the IORT field), “local” (if within the EBRT
field), “regional” (if in regional lymphatics), “peritoneal” (if seeding
occurred), and “distant” (if beyond the regional site) [10]. In our series, we had no central or local
failures. The predominant mode of
failure was regional, but not within lymph nodes.Our series reports a high rate of
gross total resections. Twenty-six (84%)
patients—fifteen treated
with preoperative radiation, and 11 treated postoperatively—were able to
undergo a GTR. On presentation, 2
patients were deemed by our surgeons to have technically unresectable tumors. Both were treated with preoperative radiation—one subsequently
had his tumor respond enough to undergo a GTR.
Both patients with technically unresectable disease eventually developed
pulmonary metastases. The patient who
had a GTR also had 2 separate metastectomies of lung metastases and remained without evidence
of further recurrent disease 29 months after initial treatment.We advocate a stringent follow-up
regimen for these patients. The National
Comprehensive Cancer Network (NCCN) guidelines recommend following patients
every 3 to 6 months for the first 2 to 3 years with CTs of the abdomen and
pelvis (with consideration of chest imaging) [28]. We routinely recommend CTs also of the chest
every 3 and 4 months for the first 2 years, as we have seen that all patients
who develop metastatic disease do so within the first 15 months of therapy. This regimen allows for identification of
patients who might be candidates for initial metastectomy for oligometastases
or systemic therapy at an earlier time for multiple pulmonary lesions. While there may be an element of lead-time
bias with this imaging regimen, we believe that, with early identification of
metastases, we can prolong disease-free intervals, while the distant disease
burden is still manageable.Many patients with RPS ultimately
fail distantly and systemic therapies have not proven to be efficacious. One potential future direction in the
treatment of RPSs mirrors the targeted therapy revolution currently occurring
with various malignancies. Fifteen of 31
patients' tumors were stained for the presence of CD-117 (c kit) and of the 5
patients tumors that demonstrated varying degrees of positivity by
immunohistochemistry, one patient received 4 months of imatinib mesylate in the
preoperative setting during her radiation therapy. However, repeat immunohistochemistry for
CD-117 was negative on the resected residual mass and no post-operative
imatinib mesylate was given. This
patient remains clinically and radiographically disease-free at 40 months.As our results demonstrate, if a
patient is to develop metastatic disease, he is at highest risk within the first years and a
half after treatment. Chemotherapy might
have a role in the early setting, and not just be reserved for patients who
have already developed metastatic disease.
Pisters et al. evaluated
the use of doxorubicin concurrent with radiation therapy, and found that one
could escalate to a dose of 50.4 Gy safely [13]. However, Glenn et al. from the National
Cancer Institute reported increased acute toxicities with the use of
postoperative triple chemotherapy (including doxorubicin) during radiotherapy
in patients with resectable RPSs, without an overall survival benefit [14].Overall, the acute toxicities
associated with the modern day use of pre- or postoperative radiation therapy were
mild. Thirty of 31 patients completed
radiation therapy as prescribed. The
patient who did not complete radiation therapy had initially presented with
metastatic disease and small bowel obstruction secondary to his large tumor. He ultimately had palliative bypass surgery
and succumbed to his distant disease. There
were three grade 3-4 acute radiation-related toxicities (all 3 in the preoperative
group), and six grade 3-4 late GI toxicities (3 in the preoperative group, 3 in
the postoperative group), with the formation of only one treatment related
bowel fistula. For comparison, Peterson et al. reported 12 cases of grade 3
or higher GI complications in her series of 87 (43 with primary disease, and 44
with recurrent disease) patients with RPS; 7 of these patients had fistula
formation [10]. In our series, 6
patients (4 in the preoperative group, 2 in the postoperative group) also
experienced late grade 3-4 infectious complications, requiring drainage of retroperitoneal
abscesses and prolonged intravenous antibiotics. Grading radiation-related toxicities in
patients with RPS is especially difficult, and even more so in patients who
present with extremely large and/or recurrent tumors. Often times multiple abdominal surgeries have
been performed—a fact alone that
dramatically raises the incidence of late toxicities. There is some toxicity that must be assumed
when treating these large tumors—without
radiation, the risk of local recurrence is unacceptably high, and the
likelihood of similar toxicities secondary to tumor growth alone is similarly high.The use of IORT has been shown to
increase local control, without adding significantly to acute and late
toxicities from surgery [9, 10, 12, 16, 18, 19]. However, peripheral neuropathy has been
documented with the clinical and experimental use of IORT to doses of ≥20 Gy [29, 30]. Importantly, the incidence of
IORT-related peripheral neuropathy is not increased with the use of external
beam radiation therapy [29, 30]. In our
cohort of patients, only one patient experienced a late grade 2 neuropathy. This patient received preoperative radiation and
IORT for her fourth and fifth locoregional failures. IORT doses of 10 to 12 Gy as utilized in our
study almost uniformly preclude the development of late neurologic sequelae. However, IORT did not appear to significantly
impact LRC, DDFS, or OS in our patients.The American College  of Surgeons Oncology Group attempted a phase III trial, which randomized
patients with resectable RPS to surgery alone versus preoperative radiation
therapy followed by surgical resection [31].
However, even with excellent planning and organization, the study was
closed because of slow accrual. Thus, a
definitive answer from a prospective randomized trial regarding the efficacy of
preoperative radiation will not be available in the foreseeable future. Future studies/trials may need to include randomization
of patients to surgery alone, preoperative radiation with surgery, and surgery
with postoperative radiation therapy. Adding
chemotherapy in the neo- or adjuvant setting, so as to reduce the risk of
developing metastatic disease, can also be considered.In summary, high dose (59.4 Gy) preoperative
or postoperative radiation therapy is safe and efficacious in the treatment of
RPSs. Based upon our experience, we
recommend the consideration of either neoadjuvant or adjuvant radiation in
patients with retroperitoneal sarcoma, as well as the possibility of IORT if
there is a high likelihood of residual microscopic or minimal gross disease at
the time of surgical resection. We also
recommend routine use of follow-up chest CT scans along with abdominal and
pelvic CT scans. Some patients who initially
present with locally recurrent disease are able to have long-term disease free
intervals when treated with radiation therapy at the time of initial recurrence. However, as patients who receive radiation
more than one time for their RPS recurrences, the severity of adverse related
events increases. Further research needs
to be done, including the development of better systemic agents to combat these
difficult-to-treat tumors.



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*Source: 824036-2009-01-29.xml*