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10.1245/s10434-006-9028-6
Annals of Surgical Oncology 13:1209-1215 (2006)
© 2006 Society of Surgical Oncology
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Original Article

The Effect of Preoperative Radiotherapy and Reconstructive Surgery on Wound Complications after Resection of Extremity Soft-Tissue Sarcomas

Jennifer F. Tseng, MD, Matthew T. Ballo, MD, Howard N. Langstein, MD, Jeffrey D. Wayne, MD, Janice N. Cormier, MD, MPH, Kelly K. Hunt, MD, Barry W. Feig, MD, Alan W. Yasko, MD, Valerae O. Lewis, MD, Patrick P. Lin, MD, Christopher P. Cannon, MD, Gunar K. Zagars, MD, Raphael E. Pollock, MD, PhD and Peter W. T. Pisters, MD

Sarcoma Center, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77230-1402, USA

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: Major wound complications (MWCs) are frequent after preoperative radiotherapy (RT) for extremity soft-tissue sarcoma (STS). We examined the rate of MWCs at a single institution with readily available reconstructive surgery.

Methods: The medical records of consecutively treated extremity STS patients treated with preoperative external-beam RT and surgical resection from June 1996 through February 2003 were reviewed. Patients underwent RT (median 50 Gy), followed by resection 4–8 weeks later. Patients believed to be at higher risk for MWC underwent wound closure by the reconstructive surgery service (RSS). MWCs included secondary operation, invasive procedure, hospital readmission, or persistent deep packing or dressing changes.

Results: A total of 173 patients underwent preoperative RT. Median age was 54 years; 51% were female; 80% had lower extremity STS. Wound closure was performed by the primary surgeon in 91 cases (53%). The RSS performed wound closure in the remaining 82 patients (47%). One or more MWCs occurred in 55 patients (32%). Wound complications were more likely in patients with lower extremity (49/138, 36%) than upper extremity (6/35, 17%) STS (P = 0.03). Among patients with lower-risk wounds closed by the primary surgical team, 29 (32%) experienced MWC, whereas in the higher-risk patients closed by the RSS, MWC occurred in 26 (32%).

Conclusions: MWCs are frequent after preoperative RT and occur more commonly in patients with lower extremity tumors. The MWC rate observed in a single-institution setting was comparable to that observed in the preoperative therapy arm of a multicenter Canadian trial. Patients believed to be at higher risk for MWCs undergoing RSS closure have MWC rates comparable to those with lower-risk wounds closed by the primary team.

Key Words: Sarcoma • Radiotherapy • Neoadjuvant • Preoperative • Wound complication • Reconstructive surgery


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Patients with soft-tissue sarcomas (STS) of the extremities are often treated with a combination of surgical resection and radiotherapy (RT).1 Both preoperative and postoperative RT have been utilized, and each treatment sequence has relative advantages and disadvantages.2,3 In particular, pre-operative therapy generally requires smaller field sizes and lower doses and may be associated with less posttreatment edema and fibrosis.2 In addition, RT administered preoperatively may allow for the administration of a lower biologically effective radiation dose.4 Despite these proposed advantages, higher rates of wound complications have been reported when surgery is performed after standard-dose (50 Gy) preoperative RT.5 Retrospectively reported rates of wound complications after preoperative RT range from 30–44%.5–9 In a recently reported Canadian multicenter randomized trial (SR.2), 35% of patients treated with preoperative RT had major wound complications (MWCs) as defined by the investigators.10

The purpose of the current study was to assess the rate of MWC occurrence after preoperative RT and surgical resection in patients with extremity STS treated at the University of Texas M. D. Anderson Cancer Center (MDACC). The MDACC is a cancer center with a multidisciplinary STS group with consistent surgical oncology, radiation oncology, and reconstructive surgery practices. The MDACC institutional treatment approach for patients with extremity STS involves frequent use of preoperative RT and a low threshold for involvement of reconstructive surgeons for soft-tissue coverage and wound closure when surgery is performed after preoperative RT.

We hypothesized that the rate of MWCs measured in a single-institution setting might be lower than that observed in the Canadian multicenter trial as a result of both the single-institution effect and consistent availability of and low threshold for involving reconstructive surgery.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Patient Characteristics
From May 1996 to February 2003, 1,625 patients with extremity STS were evaluated at the MDACC. After patients were identified from a prospective sarcoma database, we excluded all patients younger than 12 years and any who had not been treated at the MDACC with preoperative RT and surgical resection. A comprehensive retrospective review was performed of the medical records of the remaining subset of 173 adult patients. Details of radiological assessment, clinicopathological prognostic factors, radiation, chemoradiation, surgical treatment, and wound-related complications were recorded for each patient.

This study was approved by the Institutional Review Board of the MDACC. Because of the retrospective nature of the study and because permission to use records for future research had been obtained at initial patient evaluation, the need for additional written informed consent was waived.

We used the following definitions for this evaluation. A tumor was considered to be a localized primary tumor if there was no evidence of metastasis and the lesion had not been treated or only a biopsy had been performed within 2 months of presentation. Locally recurrent disease was defined as tumor at a site that had previously been treated for an extremity STS. The tumor was considered to be in the upper extremity if it was at or distal to the shoulder joint and in the lower extremity if it was in the groin or leg. Axillary tumors were analyzed with those of the upper extremity; iliac fossa tumors were excluded from analysis. Tumor size was defined as the maximum dimension obtained during three-dimensional (craniocaudad, transverse, and anteroposterior) assessment of the lesion using cross-sectional imaging performed immediately prior to referral or upon initial evaluation. For patients referred to the MDACC after an excisional biopsy had been performed, we used the recorded pathological size of the prereferral excised tumor. The anatomical depth of tumors was evaluated relative to the investing fascia of the extremity, with tumors being characterized as either superficial (T1/2a) or deep (T1/2b).11 A microscopically positive surgical margin was defined as tumor present at the inked margin of the specimen.

Preoperative Radiotherapy
Patients were treated to a median dose of 50 Gy, generally delivered in 25 2-Gy fractions. As previously described, the treatment margins on the gross tumor volume were typically 5–7 cm superior to inferior and 2–3 cm laterally.12

Surgery
The therapeutic goal of tumor-directed surgery in patients treated for gross disease was to achieve macroscopic margins of 1–3 cm. For patients whose tumor excision had been performed prior to referral to the MDACC, reexcision of the surgical bed and scar was performed whenever possible. A limb-sparing approach was undertaken in all patients, with preservation of functionally significant neurovascular structures whenever possible. Closer margins were allowed if this would permit preservation of important neurovascular structures. Vascular surgery and/or neurosurgery consultation was obtained preoperatively if nerve or vascular grafts were believed necessary to facilitate limb preservation.

The strategy used for wound closure was at the discretion of the primary surgeon, following multidisciplinary review of the case. Preoperative reconstructive surgery evaluation was obtained in any patient in whom a difficult wound closure (e.g., complex primary closure, autologous tissue transfer, or split-thickness skin grafting) was anticipated based on primary tumor anatomy and/or clinical assessment of the extent of skin and soft-tissue reaction following RT. In general, the threshold for involvement of the reconstructive surgery service was low, based on emerging data indicating that patients with radiated soft tissues are at increased risk for wound complications.5,9,10

The tumor-directed operative procedures were classified by the presence or absence of residual tumor and the status of microscopic surgical margins on final pathology. An R0 resection was defined as a macroscopically complete resection with microscopically negative surgical margins, an R1 resection was defined as a macroscopically complete resection with microscopically positive surgical margins, and an R2 resection was defined as a macroscopically incomplete resection.

End Points
MWCs were retrospectively classified using the criteria utilized in the Multicenter Trial of the National Cancer Institute of Canada (SR.2) and the Canadian Clinical Trials Group (Table 1Go).10 According to these criteria, MWC is considered to be present if one or more of the following conditions are met: (1) a secondary operation is required for wound treatment, (2) an invasive procedure is necessary for wound care, (3) readmission to the hospital is necessary for wound care, (4) deep wound packing is required at any time, and (5) prolonged dressing changes, greater than 6 weeks, are required. These criteria can be readily ascertained retrospectively and are believed to be reasonable surrogates for moderate to severe treatment-related morbidity.


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  		TABLE 1. Canadian Multicenter Trial (SR.2) MWC classification
 
Statistical Analyses
A standard software package was used to assist in statistical analysis (SPSS 11.0; SPSS Inc., Chicago, IL). Summary statistics were obtained using established methods. Differences in proportions were assessed using the chi-squared test. P < 0.05 was considered statistically significant.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patients
Review of our prospective sarcoma database yielded a total of 1,625 patients with extremity STS who had been evaluated at our institution during the study period. After we had excluded all patients younger than 12 years and those who had not been treated at the MDACC with preoperative RT and surgery, we obtained a subset of 173 adults, whose records we evaluated. Table 2Go outlines the distribution of clinicopathological factors in the 173 patients treated with preoperative RT and surgery. The median age of the study population was 54 years (range 12–92). There were 85 men (49%) and 88 women (51%). The majority of patients (84%) presented with localized primary sarcomas. Thirty-five patients (20%) presented with upper extremity sarcomas, and 138 had sarcomas of the lower extremity (80%). The median tumor size was 8.2 cm (range 1–38). Twenty-two (13%) presented with superficial tumors (T1/2a) and 151 (87%) with deep tumors (T1/2b). The most common histological subtype was malignant fibrous histiocytoma (43%). The majority of patients (79%) underwent R0 resection.


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  		TABLE 2. Clinicopathologic factors for 173 patients with extremity STS treated with preoperative RT and surgery
 
Radiation, Oncological, and Reconstructive Surgical Treatments
All 173 patients underwent treatment with preoperative RT. The median RT dose was 50 Gy (range 44–66), generally delivered over 5–6 weeks in 25 2-Gy fractions. Additionally, 102 patients (59%) received preoperative chemotherapy, generally doxorubicin and/or ifosfamide-based, administered prior to RT. Thirty patients (17%) were treated with concurrent chemoradiation (doxorubicin- or gemcitabine-based), generally as part of preoperative chemoradiation protocols.

All patients were treated by function-preserving, limb-sparing surgery; no patient underwent amputation as primary tumor treatment or for management of a treatment-related MWC. No patient had disease progression following preoperative RT to such an extent that limb-salvage surgery was no longer an option.

Surgery was performed 4–8 weeks after completion of radiation. R0 and R1 resections were performed in 136 patients (79%) and 36 patients (21%), respectively. No patient underwent an R2 resection.

Ninety-one patients (53%) with wounds felt to be at lower risk for MWC underwent closure of their wounds by the primary surgical team. Eighty-two patients (47%) were felt to have higher-risk wounds and underwent wound closure by the reconstructive surgery service. The distribution of wound closure approaches utilized is outlined in Table 3Go and included 40 split-thickness skin grafts, 46 rotational flaps, 23 free flaps, and 10 complex closures. Several patients required more than one reconstructive technique for closure. Ten additional plastic surgery procedures not directly related to wound closure were performed, including vascular and nerve grafting.


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  		TABLE 3. Types of wound closure
 
MWCs
Fifty-five patients (32%) experienced one or more MWCs during the postoperative period. The frequency of overall wound complications and wound complications stratified by anatomic site are outlined in Table 4Go. MWCswereobserved in 6 of 35patients (17%) with upper extremity sarcomas vs. 49 of 138 patients (36%) with lower extremity sarcomas (P < 0.03, chi-squared test). Twenty-six (32%) patients who underwent reconstructive surgery service closure had MWC, while 29 patients (32%) who underwent closure by the primary surgeon had MWC (Table 4Go).


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  		TABLE 4. Distribution of MWCs after preoperative radiotherapy and surgery in 55 patients by clinicopathological and treatment factors
 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
To our knowledge, this is the largest single-center report evaluating wound complication rates after the use of preoperative RT among patients with extremity STS. Our findings confirm the 30–35% risk for MWCs associated with preoperative RT and surgery. To our surprise, this MWC rate observed in a single-institution setting is comparable to the 35% rate observed in the SR.2 trial.10 However, closer examination of the Canadian trial reveals that a substantial majority of the patients were actually treated in a single center –Princess Margaret Hospital – and, thus, the comparison of our wound complication rates to those observed in the SR.2 trial may be more of a single-institution comparison than is immediately apparent. Nonetheless, taking our data together with those of the SR.2 trial, we believe that it is reasonable to counsel patients who are considering standard dose (50 Gy) preoperative RT that, although the technique may have advantages, MWCs are likely to occur in about one-third of patients so treated.

Our data also confirm that treatment-related wound complications are more common in patients with lower extremity tumors than in those with upper-extremity tumors.13–15 This observation was initially described in the SR.2 trial, where 30 of 31 MWCs observed in the 88 patients in the preoperative RT-plus-surgery arm occurred in patients with lower-extremity tumors.10 Our findings in 173 consecutively treated patients convincingly confirm that patients with lower extremity sarcomas are at greater risk than those with upper extremity tumors for MWCs after preoperative RT and surgery. The site specificity of this complication is clinically relevant and should be incorporated into individual patient treatment risk assessment and planning.

It has been hypothesized that the ready involvement of a reconstructive surgical service as an integral part of the multidisciplinary team for treating patients with STS might translate into a lower risk for wound complications.5,16–18 The results of our study do not directly support this hypothesis as we found no difference in the rate of MWCs according to what type of surgical team closed the wounds. It must be kept in mind, however, that our groups of patients were not comparable; by definition, patients with higher-risk wounds were automatically referred to the reconstructive surgery service for subsequent wound closure. Indeed, many of these patients could not have undergone limb-sparing, function-preserving surgery without involvement of a reconstructive surgeon. These patients have wounds that cannot be closed primarily under most circumstances, and many such patients would have been treated with amputation in the past – in the era prior to multispecialty limb- and function-preserving surgery.19,20 That said, it is important to note that patients with high-risk wounds who are treated with preoperative RT, surgery, and reconstructive surgery service closure still experience a clinically significant risk for MWCs (as defined by SR.2 criteria) on the order of 30–35%. It appears that involvement of a reconstructive surgeon in closure of high-risk wounds allows for limb-sparing, function-preserving surgery to be performed with wound complication rates comparable to those observed with preoperative RT and surgical resection of lower-risk wounds closed by the primary surgeon. It thus seems reasonable to conclude that patients undergoing surgical resection of a primary STS after having undergone standard-dose preoperative RT should be counseled that the risk for MWCs is site-dependent and occurs in approximately 17% of patients with upper extremity disease and 36% of those with lower extremity disease with state-of-the-art wound-closure approaches.

The criteria and methodology that we used to classify wound complications also warrant discussion. We chose to use the same criteria for classification of MWCs that were used by the Canadian investigators in the SR.2 randomized trial of pre- vs. postoperative RT.10 We used these criteria because they were reasonably objective, could be reliably discerned by retrospective review of medical records, and could be considered to be realistic indicators of patient morbidity. Because we also intended to compare our results directly to those observed in SR.2, use of the same criteria facilitated our comparisons. A possible drawback of using these criteria, however, is that there may be varying opinions as to whether some should be considered "major" wound complications. For example, the need for several weeks of dressing changes to an open granulating wound is inconvenient and adds specific economic and other patient-borne costs. However, many surgeons and patients view protracted dressing changes as a relatively minor, usually time-limited complication that is usually an acceptable outcome in exchange for the possibility of limb salvage. In this context, it is important to note that no patient in this series experienced a treatment-related wound complication that resulted in limb loss or death.

Our study was not designed to address the impact of the dose of preoperative radiation on the risk for MWCs. The median preoperative radiation dose was 50 Gy (range 44–66), reflecting our common practice of administering 50 Gy delivered over 25 fractions. Of interest, Mack and colleagues21 recently reported their experience with shorter-course, lower-dose (30 Gy), higher dose-per-fraction RT in a series of 75 patients. Their retrospectively determined wound complication rate was 15% in a cohort of patients that included 55 (73%) with lower extremity tumors. While the reports of wound complications following standard-dose preoperative radiation cannot be easily compared with the results of Mack et al., it is conceivable that shorter-course, lower total preoperative radiation dose approaches are associated with lower risks for MWCs. As outlined in a recent editorial, this hypothesis would be difficult to test directly in an equivalence trial comparing preoperative doses of 30 vs. 50 Gy,22 notwithstanding the considerable interest that patients and surgeons would have in the results of such a trial.

In summary, the results of this retrospective analysis of our experience at a single institution adds to the body of published literature that addresses the trade-off issues faced by both patients and physicians when they are choosing the sequencing of surgery and RT for the treatment of extremity STS. On the basis of our results, we believe that patients with upper extremity sarcomas should be counseled that their risk for treatment-related wound complications after standard-dose preoperative RT is lower than the 30–35% figure commonly cited; we also believe that there should be fewer reservations in offering such patients the option of preoperative RT that uses a shorter course, with a lower total radiation dose and a higher dose per fraction. Conversely, patients with lower extremity STS face more complicated relative value issues. Regardless of the relative risks for wound complications associated with preoperative radiation among these patients, it appears that the risk for MWCs after standard-dose preoperative RT is approximately 32% and that this risk is relatively fixed regardless of whether they have a lower-risk wound that can be closed by the primary surgical team or a higher-risk wound that requires a reconstructive surgical team to close the wound and facilitate limb salvage.

Our findings on the rate of treatment-related wound complications should be considered along with the risks for long-term treatment-related edema and fibrosis to facilitate counseling individual patients about the relative advantages and disadvantages associated with pre- and postoperative RT.


   FOOTNOTES
 
Presented in part at the annual meeting of the Society of Surgical Oncology, March 3–5, 2005, Atlanta, GA.

Received for publication November 2, 2005. Accepted for publication April 3, 2006.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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