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10.1245/ASO.2006.05.035
Annals of Surgical Oncology 13:508-517 (2006)
© 2006 Society of Surgical Oncology
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Original Article

Long-Term Results of Two Prospective Trials of Preoperative External Beam Radiotherapy for Localized Intermediate- or High-Grade Retroperitoneal Soft Tissue Sarcoma

Timothy M. Pawlik, MD, MPH1, Peter W. T. Pisters, MD1, Lynn Mikula, MD2, Barry W. Feig, MD1, Kelly K. Hunt, MD1, Janice N. Cormier, MD, MPH1, Matthew T. Ballo, MD3, Charles N. Catton, MD4, Julia J. Jones, MD2, Brian O’Sullivan, MD4, Raphael E. Pollock, MD, PhD1 and Carol J. Swallow, MD, PhD2

1 Department of Surgical Oncology, Unit 444, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030
2 Department of Surgery, The University of Toronto, Princess Margaret Hospital and Mount Sinai Hospital, Room 1224, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5
3 Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas 77030
4 Department of Radiation Oncology, The University of Toronto, Princess Margaret Hospital and Mount Sinai Hospital, Room 1224, 600 University Avenue, Toronto, Ontario, Canada M5G 1X5

Correspondence: Address correspondence and reprint requests to: Peter W. T. Pisters, MD; E-mail: ppisters{at}mdanderson.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: The reported data on surgery plus radiotherapy for retroperitoneal soft tissue sarcomas (RPS) have been mostly from retrospective studies. We evaluated the long-term outcome of patients with operable RPS who were treated with protocol-based preoperative radiotherapy followed by complete surgical resection.

Methods: Data from two prospective trials that included preoperative radiotherapy and surgery for patients with radiographically resectable RPS were combined to define long-term relapse rates and survival.

Results: Seventy-two patients with intermediate- or high-grade RPS were treated with preoperative radiotherapy (median dose, 45 Gy; range, 18.0–50.4 Gy). Fifty-four patients (75%) had primary RPS, whereas 18 (25%) had recurrent disease. The median tumor size was 15.5 cm. Sixty-four patients completed the planned preoperative radiotherapy; 57 (89%) underwent laparotomy with curative intent, and 54 (95%) had a macroscopically complete (R0 or R1) resection. With a median follow-up of 40.3 months, 28 patients (52%) who received preoperative radiotherapy and underwent a macroscopically complete resection had recurrences. For the 54 patients who underwent R0 or R1 resection after preoperative radiotherapy, the 5-year local recurrence–free, disease-free, and overall survival rates were 60%, 46%, and 61%, respectively. The median overall survival has not been reached (>60 months).

Conclusions: Patients with intermediate- or high-grade RPS treated with preoperative radiotherapy plus complete resection had a median survival >60 months. This compares favorably to historical data for similar patients treated with surgery alone.

Key Words: Retroperitoneal sarcoma • Preoperative • Radiation • Resection • Recurrence • Survival


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Soft tissue sarcomas are uncommon neoplasms, with an estimated incidence of 9400 cases in the United States in 2004.1 Retroperitoneal sarcomas (RPS) account for approximately 10% of soft tissue sarcomas.2–4 Currently, complete resection is regarded as the standard treatment of primary or recurrent RPS.5–9 However, even if a macroscopically complete resection can be performed, margins are often compromised because of anatomical constraints. In most reports of surgery for RPS, complete excision is achieved <70% of the time, and local recurrence occurs in approximately half of patients who undergo macroscopically complete resection.5–13 Locally recurrent disease is less likely to be completely resectable than primary disease and is associated with reduced long-term survival.14 The effect of local recurrence is reflected in diminished overall survival despite attempts at further resections.8,15,16

Because of the high rates of recurrence reported after resection of RPS, there has been evolving interest in the use of combined-modality treatment.17 Because local failure is the most common pattern of recurrence, the addition of radiotherapy has been proposed to improve local relapse–free survival and possibly overall survival rates. The use of surgery plus radiation for RPS is based on existing phase III trials that demonstrated improved local control rates for patients with extremity and trunk sarcomas treated with the combination of modalities.18,19 Patients with RPS may experience similar clinical benefits with the combination of surgery and radiotherapy.

Radiotherapy to the retroperitoneum is complex because of the frequently large field sizes and the proximity of radiosensitive structures. Preoperative radiotherapy for RPS has been proposed as being preferable to postoperative radiotherapy for several reasons20: the tumor is readily definable before surgery, the tumor displaces the radiosensitive viscera outside the treatment field, and the biologically effective dose of radiation may be lower before surgery than after surgery. To date, however, no randomized trial has examined the role of preoperative radiation for RPS. Our groups have previously reported on the feasibility and toxicity of preoperative radiation for RPS observed in two prospective single-arm trials.21,22 In this study, we combined the data from these two trials to evaluate the long-term outcome of patients with operable RPS treated with protocol-based preoperative radiotherapy followed by complete surgical resection.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Eligibility
Between March 1996 and January 2002, 94 patients with localized, primary or recurrent, histologically confirmed RPS were entered onto 2 prospective trials that included preoperative radiotherapy and complete resection (Table 1Go). The treatment protocols were approved by the University of Toronto Ethics Review Board or the Institutional Review Board of The University of Texas M. D. Anderson Cancer Center. Written informed consent was obtained from all patients before initiation of therapy. In addition, each institution also approved the retrospective review of the long-term outcome of the patients.


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  		TABLE 1. Preoperative radiotherapy protocols for RPS
 
Because low-grade RPS has a natural history different from that of intermediate- or high-grade RPS, this study focused on the 72 patients with intermediate- or high-grade sarcoma entered onto the two trials. Patients with low-grade tumors in the University of Toronto trial (n = 22) were excluded from this analysis.

Before protocol enrollment, patients were evaluated with a baseline history and physical examination, laboratory tests, computed tomography (CT) and/or magnetic resonance imaging of the abdomen and pelvis, and chest radiography or chest CT. Only patients with sarcomas that were believed to be potentially resectable on pretreatment CT or magnetic resonance imaging and with no evidence of distant metastatic disease were eligible. Patients were excluded if they had previously received radiotherapy to the abdomen or pelvis at the site of the current RPS. Exclusion criteria applied at The University of Texas M. D. Anderson Cancer Center but not at the University of Toronto were a Karnofsky performance score <70, a platelet count <100,000/µL, and a serum creatinine level >1.6 mg/dL.

Protocols
Separate study protocols were administered at each participating center to examine the effect of preoperative radiotherapy on patients with localized, potentially resectable RPS (Table 1Go).21,22 The Toronto Sarcoma Group (University of Toronto, Princess Margaret Hospital, and Mount Sinai Hospital) conducted a pilot study that evaluated the effects of preoperative external beam radiotherapy followed by complete resection and postoperative brachytherapy. The M. D. Anderson Cancer Center conducted a phase I trial to define the maximum tolerated dose of preoperative external beam radiation with concurrent fixed-dose continuous-infusion doxorubicin followed by resection and electron beam intraoperative radiotherapy (IORT).

Radiotherapy
At both centers, radiotreatment planning was performed by using three-dimensional CT with oral contrast to outline the gastrointestinal tract. The gross tumor volume was the primary or recurrent tumor as defined by CT. The radiation dose was prescribed to the isodose line that encompassed the volume of interest, which was typically 95% to 98%. Special treatment positioning techniques were used as needed on an individual basis.21,22

At the University of Toronto, Princess Margaret Hospital, and Mount Sinai Hospital, the planned preoperative radiation dose was 45 Gy. A radiation boost was administered after surgery via brachy-therapy in selected patients. The decision to place afterloading brachytherapy catheters was made during surgery and was dependent on the surgeon’s assessment of the margins at greatest risk for residual disease and the appropriate geometry for a stable planar implant. Brachytherapy catheters were placed on the resection bed at the conclusion of the resection.22 The parallel orientation of the catheters was maintained by using absorbable sutures to secured Vicryl mesh (Ethicon, Inc., Somerville, NJ).23 Catheters were spaced 1 cm apart on the surgical bed, secured with absorbable sutures to Vicryl mesh, and brought out through the skin via a separate stab wound. Typically, three to eight catheters were placed. Closed-suction drains were positioned intra-abdominally adjacent to the catheters to prevent serous weeping through the catheter sites at the level of the skin. When the patient recovered from the resection, as evidenced by the return of gastrointestinal function (usually 7 to 14 days), brachytherapy was administered with a planar implant to a dose of 25 Gy by using an afterloading iridium 192 pulsed dose rate brachytherapy unit. During the study, it became apparent that brachytherapy to the upper abdomen was associated with a high rate of significant morbidity22; the protocol was then modified, and brachytherapy was used selectively only in the lower abdomen/pelvis.

At M. D. Anderson Cancer Center, patients received low-dose doxorubicin concurrently with external beam radiotherapy for 4 to 5 weeks, depending on the total radiation dose.21 Doxorubicin 4 mg/m2 was administered as a 15- to 30-minute bolus intravenous infusion on days 1, 8, 15, and 22 (i.e., the first day of each week of radiation). After radiotherapy was completed, another cycle of doxorubicin 4 mg/m2 was given by continuous infusion for 4 days on days 1 to 4, 8 to 12, 15 to 19, and 22 to 26. The doxorubicin dose was adjusted for individual patients if needed on the basis of the toxicity experienced.21 Over the course of the study period, the radiation dose was escalated from 18.0 to 50.4 Gy. After resection of the RPS, 15 Gy of IORT was administered to the bed of the resected tumor. IORT was delivered through a 7- to 12-cm cone with the radiation dose prescribed to the 90% isodose line by using a 9-MeV electron beam. IORT was not administered if, in the judgment of the operating surgeon, the resection of the RPS had been so long or so complex that the additional operative time required for IORT might be detrimental to the patient.

Surgical Resection
Laparotomy for resection of the RPS was performed 4 to 8 weeks after completion of preoperative radiation. The goal of resection was macroscopically complete removal of the tumor, including adjacent organs as indicated on the basis of the operative findings. Patients were not eligible for either protocol if deliberate partial resection (R2) was planned. Standard histological evaluation of the resected specimen was performed. An R0 resection was defined as a macroscopically complete resection with microscopically negative pathologic margins, an R1 resection was defined as a macroscopically complete resection with microscopically positive pathologic margins, and an R2 resection was defined as a macroscopically incomplete resection.

Follow-Up
In both trials, patients were followed up with physical examination, CT of the abdomen and pelvis, and chest radiography at least every 6 months for 5 years and then annually. Patients were examined and imaged earlier if new symptoms developed between regularly scheduled follow-up visits. Recurrence was defined as the appearance of a new mass or masses as compared with baseline postoperative imaging. No patient was lost to follow-up.

Data Collection
Data obtained from each center were merged into a single database for analysis. The following data were collected for each patient: demographics; tumor histological characteristics, grade, and size; operative details; radiation dose; pathologic margin status; date and site of recurrence; date of and status at last follow-up; and date of death. Local failure was defined as disease recurrence in the abdomen, including the peritoneal cavity, retroperitoneum, or both. Distant failure was defined as recurrent disease at an extra-abdominal site or within the parenchyma of the liver.

Statistical Analyses
All data are presented as percentages of patients or the median value with ranges. The {chi}2 test was used to assess differences in variables. Recurrence and survival were measured from the date that preoperative radiation was initiated. Actuarial survival curves were constructed according to the method of Kaplan and Meier, and the log-rank test was used to assess the association of clinicopathologic and treatment variables with recurrence and survival. Statistical significance was set at P < .05 (two tailed).


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinicopathologic Characteristics
Table 2Go shows the clinicopathologic features of the 72 patients included in the study. The median patient age was 59 years (range, 21–87 years). The median pretreatment (radiographical) tumor size was 15.5 cm (range, 3.0–40.0 cm). Most patients had primary disease, and 40% had a liposarcoma.


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  		TABLE 2. Clinicopathologic features of 72 patients with RPS
 
Radiotherapy and Surgery
Thirty-three (89%) of the 37 patients treated at the University of Toronto completed planned preoperative radiotherapy and received 45 Gy. Four patients treated in Toronto did not complete preoperative radiotherapy because they died during treatment. Reasons for death were gastrointestinal ischemia (one patient; 7.2 Gy received), renal failure (one patient; 12.6 Gy received), aspiration (one patient; 14.4 Gy received), and cerebrovascular accident (one patient; 21.6 Gy received). At M. D. Anderson Cancer Center, preoperative chemoradiation (18.0–50.4 Gy) was completed in 31 (89%) of the 35 patients enrolled. Four patients did not receive the entire planned radiation dose because of rapid disease progression (one patient; 19.8 Gy received of the planned 46.8 Gy), tumor proximity to the liver (one patient; 28.8 Gy received of the planned 50.4 Gy), grade 3 anorexia (one patient; 45 Gy received of the planned 50.4 Gy), and patient refusal (one patient; 48.6 Gy received of the planned 50.4 Gy). Therefore, of the 72 patients included in the study, 64 (89%) completed the planned preoperative radiotreatment.

Seventy-five percent of patients received a total preoperative external beam radiation dose of at least 45 Gy (Table 3Go). Because of the differences in the two institutions’ protocols, patients at the University of Toronto were more likely to have received at least 45 Gy of preoperative radiation (88%) than patients treated at M. D. Anderson Cancer Center (54%). Thirty-five patients (49%; all from M. D. Anderson Cancer Center) also received doxorubicin concurrently with preoperative radiotherapy. The toxicities observed in each of the trials have been previously reported.21,22


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  		TABLE 3. Distribution of patients by preoperative radiation dose
 
Fifty-seven (79%) of the 72 patients who started preoperative radiation underwent subsequent laparotomy with curative intent (Fig. 1Go). Fifteen patients (21%) did not undergo operation: five patients because of death (four during preoperative radiotherapy as reported previously and one patient who died as a result of multisystem organ failure that developed in the postradiation period) and 10 because of disease progression. Disease progression during pre-operative radiotherapy included intra-abdominal sarcomatosis (n = 2), lung metastases only (n = 3), liver metastases only (n = 2), lung metastases plus local progression (n = 2), and lung plus liver metastases (n = 1).


Figure 1
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  		FIG. 1. Flow diagram illustrating the management of the 72 patients with localized intermediate- or high-grade RPS eligible for the 2 prospective trials included in this study. preop XRT, preoperative radiotherapy; IORT, intraoperative radiotherapy.

 
Among the 57 patients who underwent laparotomy with curative intent, macroscopically complete resection (R0 or R1) was achieved in 54 (95%). Of the remaining patients, one had a grossly positive (R2) resection, and two patients were found to have locally advanced disease at the time of operation that made resection impossible. An intraoperative or postoperative radiation boost was administered to 34 (60%) of the 57 patients who underwent operation: IORT in 22 patients (39%) and postoperative brachytherapy in 12 patients (21%).

Patterns of Recurrence
With a median follow-up of 40.3 months, 28 (52%) of the 54 patients who received preoperative radiation and underwent grossly complete resection developed recurrent disease: 17 patients (31%) with local failure, 8 patients (15%) with distant failure, and 3 patients (6%) with both local and distant failure. The median time to development of recurrence was 17.2 months (range, 3.2–30.0 months). The most common site of distant metastatic disease was the lungs (7 of 11 patients; 64%). None of the clinicopathologic factors analyzed for a possible association with overall recurrence proved to be significant, including male sex (P = .36), age >55 years (P = .68), histological subtype (P = .32), preoperative radiation dose ≥45 Gy (P = .13), and presentation with recurrent RPS (P = .15).

Survival
Local recurrence–free survival was calculated for the 54 patients who underwent grossly complete resection. At a median follow-up of 40.3 months, the median local recurrence–free survival had not been reached. The 2- and 5-year local recurrence–free survival rates were 79% and 60%, respectively (Fig. 2Go).


Figure 2
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  		FIG. 2. Local recurrence–free survival of the 54 patients who completed preoperative radiotherapy and underwent a macroscopically complete resection. At a median follow-up of 40.3 months, the median local recurrence–free survival had not been reached; the 5-year local recurrence–free survival rate was 60%.

 
The median disease-free survival in the 54 patients who underwent grossly complete resection was 33.0 months (Fig. 3Go). The 2- and 5-year disease-free survival rates were 57% and 46%, respectively. A trend toward longer disease-free survival was noted in patients who presented with primary rather than recurrent RPS (median, 56.7 vs. 27.0 months, respectively; P = .15). The 2- and 5-year disease-free survival rates for patients with primary RPS were 64% and 50%, respectively. There was also a trend toward longer disease-free survival in patients who received ≥45 Gy of preoperative radiation rather than lower doses (median, 39.0 vs. 16.3 months, respectively; P = .16). There was no association of disease-free survival with sex (P = .33), patient age (P = .66), tumor grade (P = .87), tumor size (P = .82), or treatment with IORT or brachytherapy (P = .87).


Figure 3
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  		FIG. 3. Disease-free survival of the 54 patients who received preoperative radiotherapy and subsequently underwent a macroscopically complete resection. The median disease-free survival was 33.0 months, and the 5-year disease-free survival rate was 46%.

 
The 1-, 2-, and 5-year overall survival rates for all 72 patients included in the study were 82%, 68%, and 50%, respectively (Fig. 4Go). For the 54 patients who underwent grossly complete resection of their tumor, the median overall survival had not been reached, and the 5-year overall survival rate was 61% (Fig. 5Go). No patient or tumor factor was significantly associated with overall survival. Patients who had received at least 45 Gy of preoperative radiation did, however, tend to have an improved overall median survival (not reached) compared with patients who received a lower dose (46.8 months; P = .18).


Figure 4
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  		FIG. 4. Overall survival of all 72 patients. The 5-year overall survival rate was 50%.

 

Figure 5
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  		FIG. 5. Overall survival of the 54 patients who received preoperative radiotherapy and subsequently underwent a macroscopically complete resection. The median overall survival had not been reached, and the 5-year overall survival rate was 61%.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
To date, most reported studies of RPS have been retrospective single-institution case series.2,5–13,24,25 In these studies, patients have often been treated with widely divergent therapeutic approaches, thus making conclusions regarding the effect of treatment difficult. This study is, to our knowledge, the largest report evaluating the outcomes of patients with RPS treated within the context of clinical trials. The use of prospective treatment protocols at each participating institution allowed us not only to evaluate the feasibility and safety of the treatment strategies, but also to assess more directly the disease-specific outcome of patients treated with preoperative radiotherapy and complete resection. The toxicities of preoperative radiation (previously published in detail21,22) were modest, and preoperative radiotherapy was well tolerated. In this study, of the 72 patients eligible for preoperative radiotherapy, only 2 (3%) did not receive the entire planned radiation dose because of radiation-related toxicity. One patient required a reduction in the planned preoperative radiation dose because of tumor proximity to the liver, and the other experienced grade 3 anorexia that necessitated a reduction in the planned dose. Gieschen et al.26 similarly reported that preoperative radiation is well tolerated in patients with RPS. These data provide convincing evidence to support the clinical impression that, notwithstanding the large treatment volumes associated with external beam radiotherapy for RPS, preoperative radiotherapy is well tolerated.

Most studies of RPS have reported 5-year local recurrence rates of 30% to 60% and overall survival rates of 20% to 70% in patients who underwent resection (Table 4Go).2,3,7,8,24,25 Patients with high-grade tumors, however, have been reported to have increased rates of disease recurrence and decreased overall survival, with 5-year overall survival rates ranging from 20% to 50%.2,24,25 In this study, despite the inclusion of only high-risk patients with intermediate- or high-grade tumors, patients who received preoperative radiotherapy and who underwent macroscopically complete resection had a 5-year local recurrence–free survival rate of 60% and a median overall survival that exceeded 60 months. Although direct comparison of results between studies is difficult, our results compare favorably to historical data for patients treated for RPS of comparable grades.


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  		TABLE 4. Grossly complete resection, local control, and overall survival rates in selected series of surgical resection of RPS
 
We attempted to evaluate the effect that various clinicopathologic or treatment factors had on the outcome of patients treated with preoperative radiotherapy and complete resection. No factor was significantly associated with local recurrence–free, disease-free, or overall survival. This may be due in part to the relatively small number of events (recurrence in 28 patients; death in 20) occurring during the study period. Some studies have reported that liposarcoma and leiomyosarcoma are associated with an increased risk of local recurrence compared with other histological subtypes.4,8 Other studies have reported improved local recurrence–free survival in patients who receive radiotherapy.5,7,27 In a study by the French Cancer Center Federation Sarcoma Group,7 multivariate analysis showed that postoperative radiotherapy was associated with a 3.4-fold reduction in the relative risk of local recurrence compared with surgery alone. Catton et al.5 similarly noted that patients who received adjuvant postoperative irradiation after macroscopically complete resection had a longer median locoregional recurrence-free survival than did those who had surgery alone. In addition, a dose effect was noted. Patients who received >35 Gy of radiation had a lower rate of in-field recurrences than did patients who received lower doses or no postoperative irradiation.5 In this study, a preoperative radiation dose of at least 45 Gy was associated with trends toward both longer disease-free and overall survival, although these did not reach statistical significance. Future studies with larger sample sizes are needed to determine which factors, including radiation dose, are most predictive of recurrence and survival.

Analysis of patterns of failure in this study demonstrated that even in patients with intermediate- or high-grade disease, the predominant pattern of recurrence was local failure. In fact, 20 of the 28 patients who had recurrences had local failure alone or with distant failure. Other investigators have also reported that local recurrence is the predominant form of relapse.2,5,7,8,25,28,29 Lewis et al.8 reported a 41% local recurrence rate at 5 years for a group of patients followed up prospectively after surgery for RPS of any grade. Similarly, Karakousis et al.2 reported that for patients with a minimum follow-up of 5 years, the overall rate of local recurrence was 46%, but for those with a minimum follow-up of 10 years, it was 60%. Ferrario and Karakousis25 reported a 10-year local recurrence rate of 66%. Taken together, these data emphasize that local recurrence is a major problem after surgical extirpation of RPS and provide an additional impetus for further studies of radiotherapy as a means to decrease local recurrence rates.

A recently activated American College of Surgeons Oncology Group phase III trial (ACOSOG Z9031) will better define whether the favorable outcomes of this study are a result of patient selection or true therapeutic benefit attributable to preoperative radiotherapy. In ACOSOG Z9031, patients with primary soft tissue sarcoma of the retroperitoneum or pelvis are randomized to receive either surgery alone or preoperative radiation followed by resection. Primary end points of the Z9031 trial are overall survival and progression-free survival, including progression of residual microscopic disease (i.e., local recurrence) and progression of residual macroscopic disease (i.e., progression of grossly evident disease in the subset of patients who do not undergo a grossly complete resection). An important component of ACOSOG Z9031 is the correlative science studies; tumor tissue and whole blood/serum are being collected for gene expression microarray analysis, protein microarray analysis, and serum proteomic analysis. The trial is open for intergroup participation through the National Cancer Institute’s clinical trials support unit. The accrual goal for the trial is 370 patients.

In summary, our findings demonstrate that pre-operative radiotherapy combined with surgical resection of RPS is feasible and safe. In addition, we report that patients with intermediate- or high-grade RPS treated with preoperative radiotherapy plus surgery had a median survival >60 months, which is seemingly better than that of historical controls. Although the 5-year local recurrence–free survival rate was 60%, local failure remained the predominant pattern of recurrence. On the basis of this report, as well as prospective studies of extremity sarcoma that have demonstrated improved local control with combined modality therapy, it is clear that further studies of preoperative radiotherapy plus surgery in larger cohorts of patients are warranted. Reasonably powered clinical trials are needed to detect any recurrence-free and overall survival benefit of combined-modality management. Given the rarity of RPS, the effect of investigational treatment can be determined only through multi-institution participation in large cooperative trials.

Received for publication June 3, 2005. Accepted for publication October 3, 2005.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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