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					      Adjuvant Radiation Therapy for Resectable
 Retroperitoneal Soft Tissue Sarcoma: The University of
                   Florida Experience
                      [Original Article: Sarcoma]

 Zlotecki, Robert A. MD, PhD*; Katz, Teri S. MD*; Morris, Christopher
        G. MS*; Lind, D Scott MD†; Hochwald, Steven N. MD†

From the *Department of Radiation Oncology and the †Department of
Surgery, University of Florida College of Medicine, Gainesville, Florida.
Reprints: Robert A. Zlotecki, MD, PhD, Department of Radiation
Oncology, University of Florida Health Science Center, PO Box 100385,
Gainesville, FL 32610-0385. Tel: 352-265-0287; fax: 352-265-0759;
E-mail: zlotera@ufl.edu.
Abstract

Background: In the management of retroperitoneal sarcomas it is
necessary to achieve local control to ensure survival. The role of
adjuvant radiation therapy (RT), either pre- or postoperative, remains
controversial.

Methods: Outcomes for 40 patients with retroperitoneal sarcoma
treated with surgery and postoperative RT (n = 25) or preoperative RT
(n = 15) were analyzed for variables prognostic for local control,
survival, and associated complications.

Results: Patterns of failure for patients treated by resection and
postoperative RT were local (n = 4), local and distant (n = 3), and
distant (n = 3). The failure patterns for preoperative RT cases were
local (n = 2), local and distant (n = 2); and distant (n = 4). Median
time to local recurrence in the postoperative and preoperative RT
series were 1 year and 2.5 years respectively. The margin status was
predictive for local control (P = 0.0065) and survival (P = 0.0012),
regardless of treatment sequence. Absolute 5-year survival was 12%
with positive margins versus 69% if negative. Histologic grade was
indicative of the risk for distant metastasis (low grade 8% vs high
grade 64%; P = 0.1373), and significantly predicted 5-year absolute
survival (low grade 77% vs high grade 34%; P = 0.0267).
Postoperative RT was associated with significant complications
(infection, hemorrhage, and bowel obstruction—2 cases each).

Conclusion: Compared with the surgery-alone series, adjuvant RT
appears to improve the probability of local control. Preoperative RT
may be the preferred sequence potentially to improve tumor
resectability and local–regional control with less risk of complications
than with postoperative RT.




Soft tissue sarcomas in general make up only 1% of all solid tumors.1
Retroperitoneal soft tissue sarcomas are relatively uncommon,
accounting for 15% of all soft tissue sarcomas diagnosed annually.2
Historically, patients have had a poor prognosis, with 5-year survival
rates ranging from 10 to 65%.3–9 Nearly 80% of patients present with
nonspecific gastrointestinal complaints. The primary tumors often
achieve substantial size before symptoms are investigated or the
tumor is discovered on physical or radiologic examination.1,8,10–12
Surgical resection remains the standard primary treatment of patients
with localized disease. Resectability rates in surgical series range from
25 to 95%.3,4,8–10,13–18 Wide negative margins of resection are often
difficult to obtain because of the proximity of the tumor to
unresectable critical organs and neurovascular structures, such as the
aorta, vena cava, spine, and/or extensive volumes of bowel and
mesentery. Consequently, local–regional recurrence remains the most
common cause of failure, and ultimately death, in these patients.

Adjuvant treatment that would improve the probability of local control
would thus significantly improve the likelihood of survival for patients
with retroperitoneal sarcoma. The role of adjuvant radiation therapy
(RT) has been evaluated in multiple single institutional and cooperative
group reports and still remains controversial. Several retrospective
studies have suggested that adjuvant RT may improve survival and
local control, whereas other investigators have found limited
benefit.8,9,17,19–26 The utility of intraoperative RT has also been
evaluated with overall favorable reports for safety and efficacy.27–34
The role of chemotherapy treatment, concurrent or sequenced, in the
management of retroperitoneal sarcoma remains investigational at this
time.16,35–37 In this article, we analyze our institutional experience in
the use of preoperative and postoperative RT as an adjuvant to
surgical resection in the management of patients with retroperitoneal
soft tissue sarcomas.

METHODS AND MATERIALS
Forty patients were treated for retroperitoneal soft tissue sarcomas at
the University of Florida between July 1974 and November 2003.
Criteria for inclusion in the study were as follows: a tissue diagnosis of
retroperitoneal soft tissue sarcoma, age 18 years or older, and
radiation tumor dose of more than 30 Gy administered either
preoperatively or postoperatively. Patients treated with palliative intent
were excluded from the analysis. Tumor staging was according to the
Musculoskeletal Tumor Society system.38 Pathologic grading was as
either low- versus high-grade histology. Complications were graded as
mild severity or acute time-limited side effects (resolving with
conservative treatment in <=6 months), moderate severity or of
sustained duration (resolving with conservative treatment in >6
months), and severe or chronic unresolved effects (requiring
hospitalization or surgical intervention).

Patients who received postoperative adjuvant RT were referred for
evaluation at the discretion of the surgical services based on operative
findings and patient performance status. Patients referred for
preoperative neoadjuvant RT were primarily all those seen at this
institution after 1994 who were felt to have potentially resectable
disease with no evidence of distant metastasis.

Adjuvant Radiation Therapy

Patients treated with postoperative RT typically received less than 50
Gy administered once daily at 1.8 Gy per fraction. One patient
receiving postoperative RT had a split-course of treatment because of
intractable diarrhea (Table 1). The majority of patients treated with
preoperative RT received 50.4 Gy using twice-daily fractionation at 1.2
Gy per fraction. All RT was delivered on high-energy LINAC delivery
systems using conformal techniques based on diagnostic imaging data.
Irradiation energies used were 6 to 20 MV photons and were often of
mixed configuration to optimize for tumor and tumor bed optimization.
Computed tomography-based treatment planning became standard in
1990 when available in our institution. The potential for intraoperative
placement of afterloading brachytherapy catheters for localized tumor
bed ―boost‖ irradiation became available in 1993. This method was
only used in 2 patients in whom after preoperative adjuvant irradiation
the resection margins, although microscopically negative, were felt to
be marginal on pathologic evaluation of the intraoperative frozen
section. Postoperative interstitial brachytherapy doses of 24 Gy were
prescribed at 50 cGy/hour to 5 mm using 192Ir afterloading ribbons.
Brachytherapy boost treatment was initiated on either day 4 or day 5
postoperatively.
                             TABLE 1. Treatment According to Histologic
                             Type and Grade




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Statistical Methods

All analyses were performed using the SAS system.39 The Kaplan–
Meier method was used to calculate survival estimates for local control
and absolute survival.40 Multivariate analyses were performed using
the Cox regression on selected covariates.41

RESULTS
Patient Characteristics

Patient age ranged from 18 to 80 years (median age, 57 years).
Fifteen patients were treated with postoperative adjuvant RT; 25
patients were treated with planned preoperative RT. Thirty-five
patients were treated at initial presentation and 5 patients were
treated at the time of first local recurrence after prior surgical
resection. Seven patients received adjuvant postoperative
chemotherapy. The median follow-up was 1.4 year (range, 0.2–15.5
years) for preoperative patients, 3.5 years (range, 0.6–13.6 years) for
postoperative patients, and 2.8 years (range, 0.2–15.5 years) overall.

The most common sarcoma histologic subtypes included liposarcoma
(15 patients), malignant fibrous histiocytoma (8 patients), and
leiomyosarcoma (7 patients). In the preoperative RT group, 12
patients had high-grade tumors and 12 patients had low-grade
tumors. In the postoperative RT group, 10 patients had high-grade
tumors and 5 patients had low-grade tumors (Table 2). Tumor size was
significantly different between the patients referred for preoperative
adjuvant versus postoperative RT (P = 0.0009). In the preoperative RT
group, 15 patients had tumors less than 11 cm, 7 had tumors from 11
to 20 cm, and 3 had tumors more than 20 cm. In the postoperative RT
group, 1 patient had a tumor less than 11 cm, 8 had tumors from 11
to 20 cm, and 6 had tumors greater than 20 cm.




                             TABLE 2. Radiation Dose to Tumor




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Fourteen of 15 patients referred and treated with postoperative RT
underwent a gross total resection: 8 patients (57%) had negative final
resection margins and 6 patients (43%) had microscopically positive
margins. One patient in the postoperative RT group underwent a
subtotal resection with gross positive margins. Twenty of 25 patients
treated with preoperative RT underwent a gross total resection: 17
patients (85%) had negative margins and 3 patients (15%) had
microscopically positive margins. Four of the patients receiving
preoperative RT were found to have unresectable tumors. One patient
in the preoperative RT group died of intercurrent disease
(nontreatment related) before surgery.

Patterns of Failure

Local recurrence developed in 7 of 15 patients (47%) of patients
treated with postoperative RT versus 4 of 25 patients (16%) treated
with planned adjuvant preoperative RT. In the postoperative RT group,
there were 4 patients with local failure alone, 3 patients with local and
distant failure, and 3 patients with distant metastasis alone. In the
preoperative RT group, 2 patients developed local failure alone, 2
patients experienced both local and distant failure, and 4 patients
developed distant metastasis alone. The median time to local
recurrence for patients treated with postoperative RT was 1 year
(range, 6.8 months–7.0 years) versus 2.5 years (range, 6.9 months–
4.8 years) for the preoperative RT group.

Actuarial Estimates of Local Control and Absolute Survival

The adequacy of the pathologic margins at surgical resection was
found to be a major determinant of local control. When negative
surgical margins were reported, the probability of local control at 5
years was 78%, compared with 0% for patients in whom the resection
margins were positive (P = 0.0065; Fig. 1). This was regardless of the
sequence of adjuvant RT administration. Tumor size was also related
to the probability of local control. Patients with tumors less than 10 cm
had an estimated local control of 94% at 5 years compared with 47%
for patients with larger tumors (P = 0.0085; Fig. 2) actuarial. Five-year
local control rates for the preoperative RT group verses the
postoperative RT group were 66% and 65% respectively (P = 0.1880;
Fig. 3). Although the actuarial analysis did not show a statistical
significance for local control by P value, the absolute crude recurrences
were only 4 of 25 for preoperative RT versus 7 of 25 for postoperative
RT. Patients with high-grade tumors had a higher risk of distant
metastasis (64% vs 8%), although the difference was not statistically
significant (P = 0.1373). On univariate analysis of variables predictive
for absolute survival, high histologic grade demonstrated a markedly
worse 5-year absolute survival rate of 34% versus 77% for low-grade
tumors (P = 0.0267; Fig. 4). The final pathologic margin at surgical
resection was also significantly prognostic for survival. The 5-year
absolute survival rate was 69% when negative margins were reported
versus 12% if the margins were positive (P = 0.0012; Fig. 5). All
variables tested via univariate analyses for both local control and
absolute survival are listed in Table 3. On multivariate analysis, tumor
size was the only significant variable for local control (P = 0.0310) and
margin status was the only significant variable for absolute survival (P
= 0.0030; Table 4).
FIGURE 1. Local control stratified according
to surgical margins (39 patients).




FIGURE 2. Local control stratified according
to tumor size (40 patients).




FIGURE 3. Local control stratified according
to preoperative versus postoperative RT (40
patients).
FIGURE 4. Absolute survival stratified
according to histologic grade (40 patients).




FIGURE 5. Absolute survival stratified
according to surgical margins (39 patients).




           TABLE 3. Variables Analyzed by
           Univariate Analysis
                       TABLE 4. Multivariate Analysis




Acute Radiation Side Effects

Enteritis, the most common acute side effect of RT delivered to the
abdominal and pelvic regions, occurred more frequently in the group of
patients treated with postoperative RT. Twelve of 15 patients (80%) in
the postoperative group experienced acute enteritis compared with 9
of 25 patients (36%) in the preoperative group (P = 0.0098). All
episodes of acute radiation enteritis were mild to moderate in severity
and duration, and were managed with conservative measures. No
hospitalizations or surgical interventions were required.

Significant Perioperative Surgical Complications

The majority of severe complications requiring hospitalization occurred
in the group of patients treated with postoperative RT (P = 0.0412).
Abdominal abscess occurred in 2 patients, retroperitoneal hemorrhage
in 2 patients, and small bowel obstruction in 2 patients. None of the
patients treated with planned preoperative RT experienced these
complications (Table 5).




                         TABLE 5. Significant Perioperative
                         Complications
DISCUSSION

One previous analysis of our institutional experience was published by
Kilkenny et al 42 from the University of Florida Department of Surgery.
The treatment records and results were reviewed retrospectively for
63 adult patients who underwent resection of primary retroperitoneal
sarcomas between 1970 and 1994. All referrals for adjuvant therapy
were for postoperative RT with or without chemotherapy, and it was
impossible to account for the selection bias. The majority of cases
referred for postoperative RT had high-grade tumors, and only 78% of
patients underwent complete resection. In that series achieving
negative margins of resection was also highly prognostic for survival,
and unfortunately negative resection margins were only achieved in
63% of patients. No patients were treated with any form of
preoperative or intraoperative adjuvant RT in this previous reporting.42
The conclusion of Kilkenny et al 42 was that postoperative adjuvant
therapies did not provide any significant improvement in either local–
regional control or survival.

The rationale for the current study was to reevaluate the potential
benefit of adjuvant RT, specifically comparing results obtained with
preoperative RT with those achieved by previous postoperative RT
regimens with respect to local control, survival, and treatment-
associated complications. Preoperative adjuvant RT has the potential
to provide several significant advantages over postoperative RT. These
include downsizing of the primary tumor, facilitation of surgical
resection, decreased potential for iatrogenic tumor implantation at
resection, less exposure of normal tissue because of tumor
displacement of normal structures (bowel) out of the treatment field,
and a lower effective irradiation dose requirement as tissue and tumor
oxygenation is preserved relative to the postoperative tissue hypoxia.

In 1994, based on these theoretic advantages and review of
preliminary data of series 30,31,43 utilizing adjuvant external beam RT
(EBRT) and intraoperative RT (IORT), a protocol of planned
preoperative EBRT with intraoperative evaluation for IORT was
initiated at our institution in an effort to improve local control and
survival in patients with retroperitoneal soft tissue sarcomas. By
incorporating IORT into the adjuvant RT treatment plan, the
therapeutic ratio of RT potentially may be enhanced by escalating the
dose to the disease site while reducing toxicity to adjacent critical
structures.

In 1993, the Mayo Clinic published data on the use of IORT in
conjunction with EBRT and maximal surgical resection in the treatment
of 20 patients with locally advanced soft tissue sarcomas (19 of 20
were retroperitoneal).30,43 The majority of EBRT was delivered
postoperatively and all patients had positive margins. EBRT consisted
of 45 to 60.4 Gy delivered with high-energy photons. IORT doses
ranged from 10 to 20 Gy with 9 to 18 MeV electron energies,
depending on margin status. The 2.5- and 5-year overall survival rates
were 83% and 48.5% respectively. Of the 20 patients, local recurrence
was observed in 4 (20% [1 in the IORT boost volume and 3 in the
EBRT field]).

In 1993, the National Cancer Institute published the results of 35
patients included in a prospective, randomized clinical trial comparing
experimental RT (IORT plus intravenous misonidazole and low-dose
EBRT) with conventional RT (high-dose EBRT) in the treatment of
patients with retroperitoneal sarcomas.31 EBRT was delivered after
complete tumor resection. In the experimental group (15 patients),
IORT was delivered to the tumor bed using an electron beam (11–15
MeV) to a dose of 20 Gy. Postoperatively, an additional 35 to 40 Gy
was delivered using EBRT with high-energy photons. In the
conventional group (20 patients), 35 to 40 Gy of EBRT was
administered with high-energy photons postoperatively, followed by a
boost to the tumor bed of an additional 15 Gy. Median follow-up was 8
years. Similar overall survival times were observed for both groups.
However, patients receiving conventional EBRT exhibited a higher rate
of local failure than those who received experimental RT with IORT.
Also, the number of gastrointestinal complications was significantly
greater among conventionally treated patients.

Investigators from the Memorial Sloan-Kettering Cancer Center
recently published data on 32 patients with retroperitoneal soft tissue
sarcoma prospectively treated according to a new protocol that
included maximal tumor resection, high-dose rate IORT using the
Harrison–Anderson–Mick applicator with 192Ir, and postoperative EBRT
when feasible.32,33 Median follow-up was 33 months. For patients with
complete gross resection receiving EBRT and IORT (24 of 30 patients),
the 5-year local control rate was 66% and the 5-year survival rate was
45%. Eleven of 32 patients (34%) experienced complications,
including 2 patients with peripheral neuropathy.
Thirty-seven patients were treated with preoperative EBRT (45–50 Gy)
and surgical resection with IORT at Massachusetts General Hospital.34
Gross total resection was obtained in 29 patients, of whom 16 also
received IORT. A single dose of 10 to 20 Gy was given with 9 to 15
MeV electrons. For the 16 patients undergoing gross total resection
and IORT, overall survival and local control rates were 74% and 83%
respectively. For the 13 patients undergoing gross total resection
without IORT, overall survival and local control rates were 30% and
61% respectively. The improvement in overall survival with IORT was
statistically significant (P = 0.044).

The use of intensity-modulated radiotherapy to optimize better the
efficacy of preoperative radiotherapy by dose escalation has been
evaluated at the University of Alabama by Fiveash et al.44
Radiotherapy doses to 57.5 Gy were effectively delivered without
compromising toxicity. By planning and delivery parameters, the
authors estimated that doses up to 75 Gy might be possible without
compromising nearby sensitive organs and structures.44

In the current series, adjuvant RT resulted in a higher rate of local
control and survival for patients receiving preoperative RT when
compared with patients receiving postoperative RT. However, this
difference did not reach statistical significance. Although statistical
analysis at 5 years indicated that preoperative RT resulted in a slightly
lower local control rate than postoperative RT. At the 2-year time
point, local control rates (90% for preoperative vs 65% for
postoperative RT) suggest that preoperative RT potentially may be
more beneficial (Fig. 3).

Currently the American College of Surgeons Oncology Group is
developing a randomized study to evaluate the feasibility and efficacy
of preoperative RT versus surgery alone in patients with
retroperitoneal sarcoma (American College of Surgeons Oncology Work
Group Z09031, ―A phase III randomized study of preoperative
radiation plus surgery versus surgery alone for patients with
retroperitoneal sarcomas [RPS]‖). Although a randomized trial
evaluating the use of IORT with preoperative EBRT in the management
of these patients might be of benefit, it is of concern that accrual of
sufficient patients to evaluate IORT as well would not be possible in a
timely manner, especially because questions regarding the efficacy
and safety of systemic chemotherapy to improve distant control and
survival also demand consideration.

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Key Words: adjuvant radiotherapy; soft tissue neoplasms; treatment
outcome; retroperitoneal neoplasms

				
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