Annals of Surgical Oncology 9:48-56 (2002)
© 2002 Society of Surgical Oncology
Adjuvant Brachytherapy for Primary High-Grade Soft Tissue Sarcoma of the Extremity
Kaled M. Alektiar, MD,
Dennis Leung, PhD,
Michael J. Zelefsky, MD,
John H. Healey, MD and
Murray F. Brennan, MD
From the Department of Radiation Oncology (KMA, MJZ), the Department of Biostatistics (DL), and the Department of Surgery (JHH, DMB), Memorial Sloan-Kettering Cancer Center, New York, New York.
Correspondence: Address correspondence and reprint requests to: Kaled M. Alektiar, MD, Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, 1275 York Ave., New York, NY 10021; Fax: 212-639-2417; E-mail:alektiak{at}mskcc.org
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ABSTRACT
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Background: We reviewed single-institution experience using brachytherapy alone for primary high-grade soft tissue sarcoma of the extremity.
Methods: Between July 1982 and September 1997, 202 adult patients with primary high-grade soft tissue sarcoma of the extremity were treated with limb-sparing surgery and adjuvant brachytherapy. All patients underwent complete gross resection, but the margin of resection was microscopically positive in 18% of patients. The median dose of brachytherapy was 45 Gy delivered over 5 days. Tumors located in the shoulder or groin were defined as central location. Complications were assessed in terms of wound complications, bone fracture, and peripheral nerve damage.
Results: With a median follow-up of 61 months, the 5-year local control, distant relapse–free survival, and overall survival rates were 84%, 63%, and 70%, respectively. On multivariate analysis, poor local control correlated with shoulder location, positive microscopic margins of resection, and nonshoulder upper extremity site. The 5-year actuarial rates of wound complications requiring reoperation, bone fracture, and grade 
3 nerve damage were 12%, 3%, and 5%, respectively.
Conclusions: Adjuvant brachytherapy provides adequate local control and acceptable morbidity that compares favorably with data reported for external beam radiation. Shoulder tumor location was identified as an independent prognostic factor for poor local control, mandating further improvement in the local management of these tumors.
Key Words: Brachytherapy • Soft tissue sarcoma • Extremity • High grade
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INTRODUCTION
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The local management of soft tissue sarcoma of the extremity has undergone significant changes in the last four decades. Limb-sparing surgery plus radiation has replaced amputation as the main treatment approach on the basis of a large body of literature, including a prospective randomized trial.1–3 The role of adjuvant radiation was tested in two prospective randomized trials comparing wide local excision alone to that with adjuvant radiation.4,5 The optimal form of adjuvant radiation in the management of soft tissue sarcoma of the extremity is unclear. Most of the radiation literature in soft tissue sarcoma is based on external beam radiation, with very few data on adjuvant brachytherapy. At Memorial Sloan-Kettering Cancer Center (MSKCC), adjuvant brachytherapy alone has been the method of choice for most patients with high-grade soft tissue sarcoma of the extremity. This choice is based both on the logistics of a short course of treatment and the results of a prospective randomized trial conducted at MSKCC, which showed that adjuvant brachytherapy improves local control over that with surgery alone. This improvement was limited to those patients with high-grade histology.4
The purpose of this study was to review a 15-year single-institution experience using brachytherapy as the sole form of adjuvant radiation in the management of primary high-grade soft tissue sarcoma of the extremity.
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METHODS
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Patients
Review of our prospective database between July 1982 and September 1997 identified 202 adult patients who were treated with adjuvant brachytherapy alone and who met the following criteria: primary presentation, high-grade histology, extremity location, and limb-sparing surgery. The exclusion criteria included those who underwent amputation, had recurrent tumors, had low-grade histology, or had distant metastasis at the time of presentation and those who received external beam radiation.
The mean age at the time of diagnosis was 52 years (range, 16–88 years). There were 90 (45%) female patients and 112 (55%) male patients. Tumor size was defined as the maximum diameter of the tumor at pathologic analysis. The anatomical depth of each tumor was evaluated relative to the investing fascia of the extremity, with tumors being characterized as either superficial or deep. The tumor was considered to be in the upper extremity if it was at or beyond the shoulder joint and in the lower extremity if it was at or beyond the groin. Tumor location was defined as central if the tumor originated in the shoulder or groin area (n = 25 of 202; 12%). Positive microscopic margin of resection was defined as tumor cells present at or within 1 mm of the inked margins of resection. The clinical and pathological characteristics of patients are listed in Table 1.
Surgery
The surgical technique used in this study has been previously described.4 In brief, all visible or palpable tumor was resected in an en-bloc fashion. Previous biopsy scars and drain sites, when present, were included in the resection. When the tumor was intermuscular or intramuscular, resection included one or more of the involved muscle bundles. For tumors situated near major neurovascular structures, resection was usually performed, with margins limited by the lack of expendable soft tissues to preserve function. But in 17 (8%) of 202 patients, resection of the major branches of an adjacent nerve was needed to obtain a complete gross resection. Similarly, stripping of the periosteum was needed for adequate resection in 6% (13 of 202) of patients, and resection of part of the adjacent bone was needed in 5% (11 of 202) of patients. The wound was primarily closed in 95% (191 of 202) of the patients and required tissue transfer in 5% (11 of 202).
Adjuvant Brachytherapy Techniques
The brachytherapy technique used after-loading catheters placed intraoperatively in the tumor bed. The tumor bed was evaluated simultaneously by the surgeon and radiation oncologist. A target region to be irradiated was determined by adding 2.0 cm to the superior and inferior dimensions of the tumor bed, with 1.5 to 2.0 cm added in the medial and lateral directions. After-loading catheters were implanted percutaneously, approximately 1 cm apart, in the target area. The catheters were fixed in position in the target region with absorbable sutures and were secured to the skin at the catheter exit site with buttons and nonabsorbable sutures. A drain was placed over the tumor bed, and the wound was closed in layers. Postoperatively, localization films were obtained and computerized dosimetry performed. The interval between surgery and loading of the catheters ranged from 1 to 14 days (median, 5 days), with only 16% (33 of 202) of patients being loaded before the fifth postoperative day. Most of those patients who were loaded before the fifth postoperative day were treated between 1982 and 1986, before the positive effect of delaying the loading on wound complications became apparent.6
The median dose of brachytherapy was 45 Gy (range, 5–55 Gy), with 184 (91%) of 202 patients receiving a total dose of 45 Gy. Most of those patients who received a dose smaller or larger than 45 Gy (18 of 202; 9%) did so before 1986, during the early years of our experience with brachytherapy. In 1 of 18, the dose of brachytherapy was only 5 Gy because the patient developed wound infection that required removal of the implant, and in the rest of patients (17 of 18) the dose range was 30 to 55 Gy. At MSKCC, the implant dose is prescribed to the median peripheral dose rate (MPDR), which is obtained from several computer-generated axial planes throughout the target volume. In each plane, the first isodose rate line that is continuous (i.e., no gaps) is selected, and then the lowest isodose rate line among all the planes is chosen. This is referred to as the MPDR. Prescribing the brachytherapy dose to the MPDR helps us determine the homogeneity of the implant (cold or hot spots). The dose rate ranged from .17 to .62 Gy/hour (median, .40 Gy/hour). The median duration of the brachytherapy treatment was 5 days (range, 1–8 days). The duration of treatment from the time of surgery until the end of brachytherapy ranged from 4 to 19 days, with a median of 11 days. 192Ir was used in 173 (86%) of 202 patients, and high-activity temporary 125I was used in 29 (14%) of 202 patients. 125I was generally used to limit the dose of brachytherapy to adjacent radiosensitive structures, such as the gonads, or to limit the dose to the skin.
Adjuvant chemotherapy was not routinely given to patients with primary high-grade soft tissue sarcoma of the extremity at MSKCC. Most of the patients who received chemotherapy in this study were part of ongoing trials and had tumors larger than 10 cm. The influence of adjuvant chemotherapy on outcome was not evaluated in this study.
Complications
Complications were assessed in terms of significant wound complication, bone fracture, and peripheral nerve damage. Peripheral nerve damage was graded according to the National Institute of Health’s Common Toxicity Criteria. Neurosensory toxicity was defined as follows: grade 1, mild paresthesias, loss of deep tendon reflexes; grade 2, moderate sensory loss, moderate paresthesias; grade 3, severe sensory loss or paresthesias that interfere with function; and grade 4, incapacitated. Neuromotor toxicity was defined as follows: grade 1, subjective weakness without objective findings; grade 2, mild objective weakness without significant impairment of function; grade 3, objective weakness with impairment of function; and grade 4, paralysis. The significant wound complications were defined as those wound problems requiring operative revision for coverage or threatened limb loss; persistent seroma requiring repeated aspirations, drainage, or both; wound separation >2 cm; hematoma >25 ml; purulent wound discharge; or a combination of these.
Follow-Up and Statistical Analysis
The time of follow-up was calculated from the date of the first operation at MSKCC. The median follow-up time for all 202 patients was 61 months (range, 3–198). Differences between variables were tested with the 
2 method and two-sided Fisher’s exact test. Actuarial rates were calculated with the Kaplan-Meier product-limit method.7 Comparisons of survival curves were performed with the log-rank (Mantel-Cox) test.8 Independent prognostic factors were identified by use of Cox’s stepwise regression analysis.9 For variables found to have independent prognostic value by multivariate analysis, relative risks (RR) with confidence intervals (CI) were calculated.
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RESULTS
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Patterns of Relapse
Of 202 patients, 28 (14%) developed local recurrence, with 9 (32%) of the 28 occurring after 2 years from the date of initial operation. The brachytherapy parameters such as the type of isotope used (Ir192 vs. I125), the total dose, and dose rate in the 28 patients who developed local recurrence were similar to those in patients who did not have local recurrence (Table 2). The margins of resection were positive in 9 of 28 patients with local recurrences. The tumor cells were present at the margin in six of nine patients and within 1 mm in three of nine patients. The location of local recurrence, i.e., in field, marginal, or outside the field of brachytherapy, could not be determined from this study. The treatment of local recurrence was amputation in 5 (18%) of 28, wide local excision plus further radiation in 9 (32%) of 28, wide local excision alone in 11 (39%) of 28, and biopsy only in 3 (11%) of 28. Distant metastasis developed in 78 (39%) of 202 patients, with 24 (31%) of 78 these relapses occurring after 2 years from the date of surgery. Seventy-nine (39%) of 202 patients died.
Local Control
The 5-year actuarial local control rate was 84% (95% CI, 78%–90%). In patients with negative margins of resection, the 5-year local control rate was 86% (95% CI, 81%–93%), compared with 74% (95% CI, 58%–90%) in those with positive microscopic margins (P = .04), as shown in Fig. 1. Tumor site and location also influenced the local control (Figs. 2 and 3, respectively). In patients with upper extremity lesions, the 5-year local control rate was 66% (95% CI, 52%–80%) compared with 91% (95% CI, 86%–96%) for those with lower extremity lesions (P < .001). For centrally located tumors (shoulder to groin region), the 5-year local control rate was 57% (95% CI, 38%–78%), as opposed to 88% (95% CI, 82%–94%) in those with noncentrally located tumors (P < .001). The tumor size and depth did not influence local control, as shown in Table 3. On multivariate analysis, upper extremity site (P = .001; RR, 4; 95% CI, 2–9), central tumor location (P = .01; RR, 3; 95% CI, 1–7), and positive microscopic margins (P = .02; RR, 3; 95% CI, 1–6) retained their significance as independent predictors of poor local control. But the correlation between site and location was not entirely independent. There were significantly more patients with upper extremity and central location, i.e. shoulder, than lower extremity and central location, i.e., groin (Table 4).
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FIG. 2. Local control (LC) for primary high-grade sarcoma according to site; upper extremity (UE) versus lower extremity (LE).
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FIG. 3. Local control (LC) for primary high-grade sarcoma according to location; central (axilla/groin) versus noncentral.
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Therefore, if we substitute site (upper vs. lower) and location (central vs. noncentral) with lower extremity, nonshoulder upper extremity, and shoulder, the negative effect of shoulder location becomes more pronounced. The 5-year local control rate for shoulder location was 44% (95% CI, 19%–69%), for nonshoulder upper extremity was 76% (95% CI, 61%–91%), and for lower extremity was 91% (95% CI, 86%–96%; P < .001), as shown in Fig. 4. Furthermore, on multivariate analysis, shoulder location emerged as an independent prognostic factor for poor local control with the strongest relative risk (shoulder location [P = .001; RR, 12; 95% CI, 5–29], positive margins [P = .018; RR, 3; 95% CI, 1–7], and nonshoulder upper extremity [P = .02; RR, 3; 95% CI, 1–8]).
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FIG. 4. Local control (LC) for primary high-grade sarcoma according to site/location; shoulder versus nonshoulder and upper extremity (UE) versus lower extremity (LE).
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Distant Relapse–Free Survival
The 5-year distant relapse–free survival (DRFS) was 63% (95% CI, 56%–70%). The 5-year DRFS rate was 81% (95% CI, 71%–91%) for tumors 
5 cm compared with 55% (95% CI, 46%–64%) for tumors >5 cm (P < .001).The 5-year DRFS was higher in patients with noncentral location (65% [95% CI, 58%–72%]) than central location (51% [95% CI, 30%–74%]), but that difference did not reach statistical significance (P = .08). Tumor depth, site, and margin status did not influence DRFS (Table 5).
Overall Survival
The 5-year overall survival (OS) rate was 70% (95% CI, 63%–77%). Larger tumor size was associated with poor OS. For tumors >5 cm, the 5-year OS rate was 63% (95% CI, 55%–71%), compared with 85% (95% CI, 75%–95%) for tumors 5 cm (P < .001). The 5-year OS rate was 84% (95% CI, 70%–98%) for superficial tumors, as opposed to 67% (95% CI, 60%–74%) for deep tumors (P = .07). Tumor site, location, and margin status did not influence OS (Table 6).
Complications
Significant wound complications developed in 41 (20%) of 202 patients. Wound complication requiring reoperation was seen in 23 (11%) of 202 of patients. The 5-year actuarial rate of wound reoperation was 12%, as shown in Fig. 5. Bone fracture occurred in 5 (3%) of 202 patients, with a 5-year actuarial rate of 3%. Four of these fractures were in the femur, and one was in the humerus. In patients in whom bone resection was performed (n = 11), the 5-year rate of bone fracture was 28%; in those with periosteal stripping (n = 13), the 5-year rate was 9%; and in those with intact bone (n = 178), the rate was 1% (P < .001). Nerve damage was assessed only in patients who did not have nerve resection (n = 185). The overall rate of nerve damage was 7% (13 of 185), with a 5-year actuarial rate of 7%. The rate of grade 1 neurotoxicity was 1% (2 of 185), grade 2 was 2% (3 of 185), grade 3 was 2% (3 of 185), and grade 4 was 3% (5 of 185). The 5-year actuarial rate of nerve damage grade 3 was 5%. In those eight patients with nerve damage grade 3, the total dose of brachytherapy was 45 Gy in all of them, and the dose rate ranged from .37 to .5 Gy/hour.
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FIG. 5. Actuarial complications for primary high-grade sarcoma treated with brachytherapy. *Only patients who did not have nerve resection were included.
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DISCUSSION
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Most of the initial experience with adjuvant radiation in the management of soft tissue sarcoma of the extremity has revolved around the use of external beam radiation.10,11 Adjuvant brachytherapy, especially when used alone, is an attractive alternative.12 Brachytherapy patients usually leave the hospital within 2 weeks of operation, having completed all their treatment. Patients undergoing external beam radiation require 5 to 7 weeks of treatment plus a 2- to 4-week interval from operations. The evaluation of the tumor bed at the time of the operation, by both surgeon and radiation oncologist, can far exceed any imaging modality in accuracy, and the rapid dose fall-off with brachytherapy spares more normal tissue than external radiation. Financially, Janjan et al.13 reported savings of US$1000 per patient treated with brachytherapy as compared with external irradiation.
The initial experience with adjuvant brachytherapy at MSKCC was reported by Hilaris et al.14 in 1982, and on the basis of these encouraging results, a prospective randomized trial was initiated. The aim of this trial was to determine whether adjuvant brachytherapy was needed after complete gross resection. One hundred sixty-four patients were enrolled; 78 patients were randomized to adjuvant brachytherapy, and 86 patients were randomized to no further therapy. With a median follow-up time of 76 months, the 5-year actuarial local control rates were 82% and 69% in the brachytherapy and no brachytherapy groups (P = .04), respectively. This improvement in local control was, however, limited to patients with high-grade histology. For this group, local control for the brachytherapy arm was 89% vs. 66% for surgery alone (P = .0025). There was no improvement in local control for patients with low-grade tumors.4
Other institutions have also reported their experience with brachytherapy in soft tissue sarcoma.15,16 However, in most of them, brachytherapy was only as a boost and not as the sole form of adjuvant radiation. In this series, 202 patients with primary high-grade soft tissue sarcoma of the extremity were treated with adjuvant brachytherapy alone. With a median follow-up of 61 months, the 5-year local control was 84% (95% CI, 78%–90%). This rate was significantly influenced by the status of the microscopic margin of resection. The 5-year local control was 86% (95% CI, 81%–93%) in patients with negative margin and 74% (95% CI, 58%–90%) in those with positive margin (P = .04). Tanabe et al.,17 from the M. D. Anderson Cancer Center, reported on 95 patients treated with preoperative external beam radiation with a 5-year local control rate of 83%. In those patients with positive margin of resection, the 5-year local control rate was 62%, compared with 91% in those with a negative margin (P = .005). The adverse effect of positive microscopic margins of resection on local control has been reported by others.18,19
In addition to margin status, the tumor site also influenced local control in this series. Upper extremity tumors had a 5-year local control rate of 66% (95% CI, 52%–80%), as opposed to 91% (95% CI, 86%–96%) for lower extremity (P < .001). The relative lack of expandable tissues in the upper extremity compared with the lower extremity could explain such a difference in local control. Such a correlation between poor local control and tumor site in the upper extremity has been reported.20 In this series, if the tumor was located in the shoulder or groin region (central location), the 5-year local control rate was 57% (95% CI, 38%–78%), compared with 88% (95% CI, 82%–94%) in those with noncentral locations (P < .001). Central tumor location was an independent prognostic factor for poor local control on multivariate analysis (P = .01; RR, 3; 95% CI, 1–7). However, this poor local control for central location was largely driven by shoulder tumor location. The 5-year local control rate for shoulder location in this series was 44% (95% CI, 19%–69%); this was also an independent prognostic factor for poor local control (P = .001; RR, 12; 95% CI, 5–29). Suit et al.21 have shown that tumors located in the shoulder region have a 5-year local control of 71% compared with 84% for those with thigh lesions. What contributes to poor local control in patients with shoulder location is unclear. In this series, the brachytherapy treatment characteristics (total dose, dose rate, and whether 192Ir or 125I was used) for the 28 patients who developed local recurrences compare favorably with the characteristics of those who did not experience local recurrence. Therefore, we cannot attribute these local failures to lower total doses (none of the 28 patients received a dose <40 Gy) or to cold spots, which would have manifested themselves with lower dose rates (none of them had a dose rate <.37 Gy/hour). Nor could it be attributed to the lower radiation energy emitted when 125I was used.
Most institutions that use brachytherapy in the treatment of soft tissue sarcoma of the extremity use it as a boost that is supplemented with external beam radiation.15,16,22 One of the reasons cited for not using brachytherapy alone is the concern about wound complications.15 However, in this series, the overall significant wound complication rate was 20%, with a 5-year actuarial rate of 12% for wound complications requiring reoperation. Further, in a previous report from our institution, the rate of significant wound complication with brachytherapy alone was 16%, compared to 27% with brachytherapy and external beam radiation (P = .39).23 These rates of wound complication with brachytherapy alone also compare very favorably with those reported with surgery alone and with preoperative or postoperative external beam radiation.24–26 In a randomized prospective trial from Canada comparing preoperative with postoperative external beam radiation, wound complication was a primary end point of that trial. Wound complications were defined as secondary wound surgery, hospital admission for wound care, and deep packing or prolonged dressings within 120 days of tumor resection. The investigators found that the rate of wound complications was significantly higher with preoperative radiation (35% vs. 17%; P = .01).27
The effect of adjuvant radiation on the development of bony fracture has been reported in the literature, but the data are scant. Stinson et al.28 reported on 145 patients with soft tissue sarcoma who underwent limb-sparing surgery and postoperative radiation with or without chemotherapy and found a 6% fracture rate. Brant et al.29 reported a 7.6% rate of pathological fracture in patients treated with preoperative radiation. For patients treated with adjuvant brachytherapy in the MSKCC randomized trial, the rate of fracture was 5%, compared with 0% in the control arm. This difference, however, was not statistically significant (P = .18).30 Lin et al.31 evaluated 205 patients with soft tissue sarcoma of the thigh to determine the contributing factors to pathological fracture of the femur in patients treated with adjuvant radiation. The 5-year actuarial risk was 8.6%, which on univariate analysis correlated with periosteal stripping (P = .0001), location in the anterior compartment (P = .008), female sex (P = .01), the use of chemotherapy (P = .02), age 50 years (P = .03), and the use of external beam radiation instead of brachytherapy (P = .04). On multivariate analysis, only periosteal stripping retained significance (P = .01). In this series the 5-year actuarial rate of bone fracture with brachytherapy alone was 3%. In patients with intact bone, the 5-year rate was 1%, and in those with periosteal stripping it was 9%.
The other type of complication encountered with adjuvant radiation is peripheral nerve damage. Unlike wound complications and bone fracture, peripheral nerve damage is poorly reported in the literature. LePechoux et al.32 reported a rate of 1.6% of peripheral nerve damage in 62 patients treated with postoperative radiation. Brant et al.29 reported a 3.4% rate for patients treated with preoperative radiation. In the control arm (surgery alone) of the MSKCC randomized trial, the rate was 5%, compared with 9% in the brachytherapy arm (P = .5).30 In this series, the overall rate of nerve damage was 10% (19 of 185), but the 5-year actuarial rate of grade 3 peripheral nerve damage was 5%. The total dose of brachytherapy in all the patients with significant nerve damage was 45 Gy, and the dose rate, which should reflect the presence of hot spots, was well within the acceptable range (.37–.5 Gy).
In conclusion, adjuvant brachytherapy provides good local control with acceptable morbidity in high-grade soft tissue sarcoma of the extremity. Whether brachytherapy is superior to external beam radiation could not be determined from these data. The short duration of this treatment is an attractive aspect that might prove useful when designing future adjuvant chemotherapy trials, because the issue of how best to try to sandwich the radiation and chemotherapy becomes moot. Patients with shoulder tumors seem to have lower rates of local control, an issue that needs further investigation to determine the optimal method of local therapy in this group of patients.
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Acknowledgments
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Supported by National Institutes of Health Grant CA-47179 (M.F.B.).
Received for publication June 15, 2001.
Accepted for publication August 16, 2001.
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ABSTRACT
INTRODUCTION
