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© 2002 American Society for Clinical Oncology Adjuvant Radiation for Stage II-B Soft Tissue Sarcoma of the ExtremityByFrom the Departments of Radiation Oncology, Biostatistics, and Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Kaled M. Alektiar, MD, Memorial Sloan-Kettering Cancer Center, Department of Radiation Oncology, 1275 York Ave, New York, NY 10021; email: alektiak{at}mskcc.org
PURPOSE: Adjuvant radiation therapy (RT) has been shown to improve local control in patients with high-grade soft tissue sarcoma (STS) of the extremity. This study sought to define the optimal management in patients with stage II-B (high-grade, size  5 cm) tumors. PATIENTS AND METHODS: Between July 1982 and December 1998, 204 adult patients with primary stage II-B STS underwent limb-sparing surgery with negative microscopic margins. Eighty-eight patients (43%) received RT; 116 (57%) did not. The RT and no-RT groups were balanced with regard to age, site (upper v lower extremity), whether patients had prior unplanned excision, and location (central, ie, shoulder/groin v noncentral). The RT group had more deep tumors (P = .03). Adjuvant RT was delivered with brachytherapy in 60% and external-beam radiation in 40% of patients. RESULTS: With a median follow-up of 67 months, the 5-year local control, distant relapse-free survival, and disease-specific survival rates were 82%, 80%, and 88%, respectively. There was no significant difference in local control between the RT and no-RT groups (84% v 80%, respectively, P = .3). Tumor depth, site, and prior unplanned excision did not correlate with local control. The only independent predictors of poor local control were central tumor location (relative risk [RR] = 3; 95% confidence interval [CI], 2 to 7; P = .005) and age more than 50 years (RR = 6; 95% CI, 2 to 13; P = .001). CONCLUSION: In this retrospective study, adjuvant RT did not significantly improve local control in patients with stage II-B STS of the extremity. The outcome of patients with central tumor location was poor, and efforts to identify the optimal local treatment approach for such patients are warranted.
TWO PROSPECTIVE randomized trials comparing limb-sparing surgery alone to adjuvant radiation (RT) have shown an improvement in local control in patients with soft tissue sarcoma (STS) of the extremity.1,2 Yet there is still considerable debate in the literature whether or not all patients need adjuvant RT. Several authors have evaluated the role of RT in various subsets of patients. Rydholm et al3 used tumor depth (subcutaneous or intramuscular) as a criterion to omit RT. Karakousis et al4 used 2-cm gross surgical margin as the criterion. Baldini et al,5 on the other hand, used a combination of favorable clinical factors.
Most authors have advocated small tumor size ( The purpose of this study was to determine whether the addition of RT to surgery alone would improve the local control in patients with primary high-grade STS of the extremity treated with limb-sparing surgery and in whom the margins of resection were negative. In addition, this study attempted to identify some of the prognostic factors in this group of patients that might impact the outcome in terms of local control, distant relapse-free survival (DRFS), and disease-specific survival (DSS).
Patients Review of the prospective database at Memorial Sloan-Kettering Cancer Center (MSKCC) between July 1982 and December 1998 identified 204 adult patients with stage II-B STS of the extremity. All of these patients met the following criteria: (1) surgery type was limb-sparing, (2) tumor size 5 cm, (3) high-grade histology, (4) extremity site, (5) primary presentation, and (6) negative microscopic margins of resection. Positive microscopic margin of resection was defined as tumor cells present at or within 1 mm of the inked margins of resection. The exclusion criteria included those who underwent amputation instead of limb-sparing surgery, recurrent tumors, low-grade histology, and those with distant metastasis at the time of presentation. The clinical, pathologic, and treatment characteristics of patients are listed in Table 1.
The mean age at the time of diagnosis was 49 years (range, 16 to 89 years). Of 204 patients, 101 (49%) were female and 103 (51%) were male. Tumor size was defined as the maximum diameter of the tumor at pathologic analysis. Actual tumor size measurements, other than being 5 cm, were available in 197 (97%) of 204 patients. Tumor size ranged from 1 to 5 cm, with a mean of 3.2 cm. The tumor size was 3 cm in 109 (55%) of 197 patients and more than 3 cm in 88 (45%) of 197. The anatomic 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 and in the lower extremity if it was at or beyond the groin. Tumor location was defined as central if the epicenter of the tumor originated in the shoulder or groin area (28 of 204, 14%).
Surgery
Radiation The technique of BRT has been previously described.10 In brief, the BRT technique used after-loading catheters placed intraoperatively in the tumor bed. The surgeon and radiation oncologist evaluated the tumor bed simultaneously. A target region to be irradiated was determined by adding 2.0 cm to the superior and inferior dimensions of the resected tumor bed, with 1.5 to 2.0 cm added in the medial and lateral directions. The after-loading catheters were placed intraoperatively, approximately 1 cm apart, in the tumor bed. The catheters were fixed in position in the target region using absorbable sutures and 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 was performed. BRT alone was given to 47 of 53 patients, and BRT as a boost, combined with EBRT, was given to six of 53 patients. The dose of BRT alone was 45 Gy in 42 (89%) of 47 patients at a median dose rate of 0.41 Gy/h. Five out of 47 patients received BRT alone to a dose less than 45 Gy. Three received 40 Gy, one received 30 Gy, and one received only 5 Gy because of a wound complication that required removing the implant prematurely. When BRT was used as a boost (six of 53 patients), the dose was 16 to 30 Gy, and the EBRT dose was 35 to 50 Gy. For the purpose of this analysis, these six patients who received BRT as a boost were included in the BRT group (n = 53, 47 + six patients). Among patients with postoperative EBRT (n = 35), treatment was given 4 to 6 weeks after the surgery to a total median dose of 63 Gy (range, 30 to 70 Gy) at 1.8 to 2 Gy per fraction. The initial target volume included the tumor bed plus 5- to 10-cm margins to a dose of 45 to 50 Gy. This was usually followed by one or two cone-downs to bring the median total dose to 63 Gy.
Chemotherapy
Follow-Up and Statistical Analysis
Associations between variables were tested using the
The RT and no-RT groups were well balanced with regard to age, tumor site (lower v upper extremity), location (central v noncentral), and whether patients had a prior unplanned excision. There were, however, a significantly higher percentage of deep-seated tumors in the RT group compared with the no-RT group (66% v 50%, respectively, P = .03), as shown in Table 2.
The extent of surgical resection was similar in the RT and no-RT groups. No intentional attempts were made to adjust the extent of resection based on whether or not the patient was to receive adjuvant RT. The mean tumor size in the RT group was 3.4 cm (range, 1 to 5 cm), and it was 3.1 cm (range, 1 to 5 cm) in the no-RT group. Actual tumor size measurements, other than being 5 cm, were not known in one (1%) of 88 patients in the RT group compared with six (5%) of 116 in the no-RT group (P = .2). The RT and no-RT groups were also matched according to tumor size versus more than 3 cm. The time frame within which the patients were treated was also similar for the RT and no-RT groups (1982 to 1997). The median follow-up time for the RT group was 68 months compared with 66 months for the no-RT group.
Patterns of Failure
Local Control
The only predictors of local failure were age greater than 50 years old and central tumor location (shoulder/groin). The 5-year local control was 69% (95% CI, 58% to 81%) for patients who are more than 50 years old as opposed to 91% (95% CI, 86% to 97%) for those who are less than 50 years old (P = .001), as shown in Fig 2. The 5-year local control rate was 63% (95% CI, 43% to 84%) for central location compared with 85% (95% CI, 80% to 92%) for noncentral location (P = .007), as shown in Fig 3. In the subset of patients with noncentral location, the 5-year local control rate was 85% (95% CI, 77% to 93%) for lesions located beyond the elbow/knee compared with 85% (95% CI, 76% to 94%) for those located at or proximal to the elbow/knee (P = .7). The tumor depth, site (upper v lower extremity), and whether or not the patient had a prior unplanned excision did not significantly impact our local control (Table 3). On multivariate analysis, central tumor location (RR = 3; 95% CI, 2 to 7; P = .005) and age more than 50 years (RR = 6; 95% CI, 2 to 13; P = .001) retained their significance as predictors of poor local control.
Because of the imbalance between the RT and no-RT groups according to depth, the influence of RT on local control was evaluated only in patients with deep tumors (n = 116). In this subset of patients with deep tumor, the RT (n = 58) and no-RT (n = 58) groups were balanced according to age (P = .8), site (P = .4), location (P = .9), and whether they had had a prior unplanned excision (P = .7). The 5-year local control rate in patients with deep tumors who received RT was 83% (95% CI, 72% to 94%) compared with 80% (95% CI, 69% to 92%) in those with deep tumors but who did not get RT (P = .6). Furthermore, on multivariate analysis for all patients with deep tumors only, age more than 50 years old (RR = 6; 95% CI, 2 to 13; P = .001) and central location (RR = 3; 95% CI, 2 to 7; P = .005) were the two independent prognostic factors for poor local control.
The influence of actual tumor size on local control was also evaluated. For patients with tumor size
DRFS and DSS
Complications Complications were assessed in terms of wound complications requiring re-operation. Out of 204 patients, four patients (2%) developed such wound complications. The 5-year actuarial rate was 2% (95% CI, 0% to 4%). In the RT group, the 5-year actuarial rate was 3% (95% CI, 0% to 7%) compared with 2% (95% CI, 0% to 5%) in the no-RT group (P = .7).
The role of adjuvant RT in the management of STS of the extremity has been established through multiple retrospective reviews but, more importantly, through three prospective randomized trials.1,2,10,14-17 In one trial, amputation was compared with limb-sparing surgery and RT, and in the other two trials, limb-sparing surgery alone was compared with limb-sparing surgery plus adjuvant RT.1,2,14 What remains debatable is whether there is a subset of patients in which adjuvant RT could be omitted.
One subset that has been identified is patients with tumor size
Generally most authors would not recommend adjuvant RT to patients with small low-grade tumors or those who underwent amputation because of low rate of local recurrence. On the other hand, patients with positive margin of resection are generally given adjuvant RT because of their poor local control. In the Geer study, of patients with tumor In the current series, patients with low-grade tumors, those who underwent amputation, and those with positive margins of resection were excluded. The inclusion of patients with low-grade histology or those who underwent amputation may have diluted the true impact of adjuvant RT. Patients with positive margins were excluded because most of them receive adjuvant RT at our institution. Including them would have introduced a significant bias into the study because positive margin status is a well-known predictor of poor local control even in patients who received RT.19,20 But despite these strict inclusion criteria, the 5-year local control rate was 80% for patients who had surgery alone and 84% for those who had adjuvant radiation (P = .3). An attempt was made to try to account for any imbalance between the RT and the no-RT groups based on known prognostic factors, time period within which the two groups were treated, as well as some treatment parameters. The two groups were matched according to age, site (upper v lower extremity), location (central v noncentral), and prior unplanned excision. The only imbalance was related to tumor depth, there was significantly higher number of patients with deep tumors in the RT group compared with the no-RT group (66% v 50% respectively, P = .03). It is possible that the depth of tumor may have influenced the decision on whether to give adjuvant RT or not. But tumor depth as a prognostic factor did not influence local control on univariate or multivariate analysis. In addition, the influence of tumor depth on DRFS and DSS in this study was only marginal (P = .06, 0.09 respectively). In the current American Joint Commission on Cancer staging system, stage II-B STS included patients with deep as well as superficial tumors, signifying that depth may not be as crucial in this group as it is in other stage groups. But to reduce this potential bias further, the impact of adjuvant RT on local control was evaluated on patients with deep tumors only (116 of 204 patients). Adjuvant RT was still not significant on univariate (83% RT v 80% no-RT, respectively, P = .6) or multivariate analysis.
The time period within which the two groups were treated was identical (1982 to 1997). The median follow-up time was 68 months for the RT group and 66 months for the no-RT group. Is it possible that the RT dose in those who developed local recurrence was inferior? Out of the 33 patients who developed local recurrence, 12 have had RT. Of these 12 patients, five received EBRT to a dose that was
What if preoperative EBRT was used instead of postoperative EBRT or BRT? Such comparison between postoperative and preoperative RT was addressed by Cheng et al,21 who reviewed the University of Minnesota experience in 112 patients with primary STS of the extremity. In the subset of patients with tumors that were
The lack of difference in local control between the RT and no-RT groups could be attributed to other prognostic factors such as the size of negative margins and the actual tumor sizes. What constitutes an adequate negative margin of resection for patients with STS of the extremity remains undefined. Sadoski et al19 reported a 5-year local control of 97% for patients with negative margin more than 1 mm, 96% for patients with negative margins less than 1 mm, and only 83% for patients with positive margin at the inked surface. In the surgery arm of the National Cancer Institute prospective randomized trial, Yang et al2 reported a local recurrence rate of three out of 14 patients in those with 1- to 10-mm negative margins compared with zero out of five patients in those with more than 10-mm margins, a difference that is unlikely to be statistically significant.2 Based on the available, albeit sparse, data in the literature, the local control does not seem to be influenced by the actual size of the negative margins in patients treated with surgery alone or with adjuvant RT. With regard to actual tumor size, in this study the mean was similar between the two groups (RT: 3.4 cm; no-RT: 3.1 cm), and local control was not influenced based on tumor size less than versus more than 3 cm (P = .7). Other investigators who did evaluate local control according to size cutoff other than 5 cm showed no significant difference in local control. Sadoski et al,19 using preoperative RT, reported a 5-year local control of 100% in seven patients with tumor size Obviously, the only way to determine whether adjuvant RT is truly needed for patients with stage II-B STS of the extremity would be through a prospective randomized trial. Such a trial, however, would be difficult to conduct because of the large sample size required to demonstrate a small, if any, improvement in local control with the addition of adjuvant RT to surgery alone. Even though a retrospective study has its limitations in trying to determine the true impact of an adjuvant treatment because of the inherent biases, it could identify some of the potential prognostic factors that might influence the outcome. In the current series, age greater than 50 years old emerged as an independent prognostic factor for poor local control (RR = 6; 95% CI, 2 to 13; P = .001) but not for DRFS or DSS. Similar correlation between older age and outcome was reported by LeVay et al.22 The influence of anatomic location on outcome was significant in this series. The 5-year local control rate was only 63% in patients with central tumors (shoulder/groin) compared with 85% for patients with noncentral location (P = .007). Central location was also an independent prognostic factor for poor local control (RR = 3; 95% CI, 2 to 7; P = .005) and marginal for DSS (RR = 3; 95% CI, 1 to 7; P = .056) on multivariate analysis. Suit et al23 have also shown that tumors located in the shoulder region have a 5-year local control of 71% compared with 84% for those with thigh lesions.23 It is unclear why tumors located near the shoulder or groins do not do as well as more distally located tumors. Perhaps adequate wide local excision is not as feasible as in the thigh because of the decision to preserve the neurovascular bundle. Increasing the dose of BRT beyond 45 Gy or that of postoperative EBRT beyond 70 Gy could cause a significant increase in the complication rate of the underlying normal structures such as lungs, viscera, and neurovascular bundles. Whether preoperative RT in those settings is more beneficial than BRT or postoperative RT cannot be determined from this study. But it has the potential of improving the resectability of these tumors while limiting the dose of RT to 50 Gy.
For patients with sarcoma In summary, based on this retrospective study with its inherent limitations, adjuvant RT, when compared with surgery alone did not improve local control in patients with stage II-B STS of the extremity who had negative margins of resection. It is important to emphasize, however, that the findings from this study are only applicable to a selected group of patients, not to those with positive margins of resection or those who have had only tumor excision without subsequent re-excision. In addition to older age, central tumor location correlated with poor local control. Thus, further investigations to try to identify the optimal treatment approach for such patients are warranted.
Supported by grant no. CA-47179 from the National Institutes of Health, Bethesda, MD. We thank Leela Nathan for editorial assistance.
1. Pisters PW, Harrison LB, Leung DH, et al: Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 14: 859-868, 1996
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Yang J, Chang A, Baker A, et al: Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity. J Clin Oncol 16: 197-203, 1998 3. Rydholm A, Gustafson P, Rooser B, et al: Limb-sparing surgery without radiotherapy based on anatomic location of soft tissue sarcoma. J Clin Oncol 9: 1757-1765, 1991[Abstract] 4. Karakousis CP, Emrich LJ, Rao UN, et al: Feasibility of limb salvage and survival in soft tissue sarcomas. Cancer 57: 484-491, 1986[CrossRef][Medline]
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Baldini EH, Goldberg J, Jenner C, et al: Long-term outcomes after function-sparing surgery without radiotherapy for soft tissue sarcoma of the extremities and trunk. J Clin Oncol 17: 3252-3259, 1999
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Geer R, Woodruff J, Casper E, et al: Management of small soft-tissue sarcoma of the extremity in adults. Arch Surg 127: 1285-1289, 1992 7. Respondek P, Pollack A, Feig BW, et al: Prospective trial of conservative surgery and selective use of radiotherapy for AJCC T1 extremity and trunk soft tissue sarcomas. Sarcoma 1: 219, 1997 (abstr)
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Pisters P, Leung D, Woodruff J, et al: Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 14: 1679-1689, 1996
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Coindre J, Terrier P, Bui N, et al: Prognostic factors in adult patients with locally controlled soft tissue sarcoma: A study of 546 patients from the French Federation of Cancer Centers Sarcoma Group. J Clin Oncol 14: 869-877, 1996 10. Harrison L, Franzese F, Gaynor J, et al: Long-term results of a prospective randomized trial of adjuvant brachytherapy in the management of completely resected soft tissue sarcomas of the extremity and superficial trunk. Int J Radiat Oncol Biol Phys 27: 259-265, 1993[Medline] 11. Kaplan EL, Meier P: Non-parametric estimation from incomplete observations. J Am Stat Assoc 53: 457-481, 1958[CrossRef] 12. Mantel N: Evaluation of survival data and two new ranks order statistics arising in its consideration. Cancer Chemother Rep 50: 163-170, 1966[Medline] 13. Cox DR: Regression models and life-tables. J R Stat Soc B 34: 187-220, 1972 14. Rosenberg S, Tepper J, Galtstein E, et al: The treatment of soft-tissue sarcoma of the extremities: Prospective randomized evaluations of (1) limb-sparing surgery plus radiation therapy compared with amputation and (2) the role of adjuvant chemotherapy. Ann Surg 196: 305-315, 1982[Medline] 15. Suit H, Russell W, Martin R: Management of patients with sarcoma of soft tissue in an extremity. Cancer 31: 1237-1245, 1973[CrossRef][Medline] 16. Lindberg R, Martin R, Romsdahl M, et al: Conservative surgery and postoperative radiotherapy in 300 adults with soft-tissue sarcomas. Cancer 47: 2391-2397, 1981[CrossRef][Medline] 17. Suit H, Sprio I: Role of radiation in the management of adult patients with sarcoma of soft tissue. Semin Surg Oncol 10: 347-356, 1994[Medline]
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Fleming J, Berman R, Cheng S, et al: Long-term outcome of patients with American Joint Committee on Cancer stage IIB extremity soft tissue sarcomas. J Clin Oncol 17: 2772-2780, 1999 19. Sadoski C, Suit CH, Rosenberg A, et al: Preoperative radiation, surgical margins, and local control of extremity sarcomas of soft tissues. J Surg Oncol 52: 223-230, 1993[Medline] 20. Pollack A, Zagars G, Goswitz M, et al: Preoperative vs. postoperative radiotherapy in the treatment of soft tissue sarcomas: A matter of presentation. Int J Radiat Oncol Biol Phys 42: 563-572, 1998[CrossRef][Medline] 21. Cheng E, Dusenbery K, Winters M, et al: Soft tissue sarcomas: Preoperative versus postoperative radiotherapy. J Surg Oncol 61: 90-99, 1996[CrossRef][Medline] 22. LeVay J, O’Sullivan B, Catton C, et al: Outcome and prognostic factors in soft tissue sarcoma in the adult. Int J Radiat Oncol Biol Phys 27: 1091-1099, 1993[Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. Survival rates were calculated using the Kaplan-Meier product-limit method.
60 Gy in five of five, the dose of BRT alone was 45 Gy in four of five, and 40 Gy in one of five patients. For the two patients who received BRT + EBRT the doses were 20 + 50 Gy and 30 + 26 Gy, respectively. The actual tumor size of the primary tumors was known in all 33 patients (mean, 3.3 cm; range, 1 to 5 cm). The treatment for local recurrence was biopsy only in five (15%) of 33 patients, wide local excision alone in 12 (37%) of 33, wide local excision and RT in 11 (33%) of 33, and amputation in five (15%) of 33. Of the five amputations, three were in the RT group and two were in the no-RT group. Distant recurrence developed in 18% (37 of 204) of patients. The total number of deaths was 43 (21%) of 204 patients, and 25 of these 43 deaths were confirmed to be related to sarcoma. 
