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10.1245/ASO.2005.03.045
Annals of Surgical Oncology 12:228-236 (2005)
© 2005 Society of Surgical Oncology
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Original Article

Prognostic Factors for Survival in Patients With Locally Recurrent Extremity Soft Tissue Sarcomas

Fritz C. Eilber, MD1, Murray F. Brennan, MD1, Elyn Riedel, MA2, Kaled M. Alektiar, MD3, Cristina R. Antonescu, MD4 and Samuel Singer, MD1

1 Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021
2 Department of Biostatistics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021
3 Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021
4 Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021

Correspondence: Address correspondence and reprint requests to: Samuel Singer, MD; E-mail: singers{at}mskcc.org.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Background: Factors prognostic for survival in patients with locally recurrent extremity soft tissue sarcomas (STS) are poorly defined, thus making it difficult to identify high-risk patients who may benefit from adjuvant therapy.

Methods: A total of 1421 patients underwent surgical treatment for primary extremity STS at a single institution between 1982 and 2002. Of these, 179 (13%) patients underwent complete surgical resection of an isolated local recurrence and were the subjects of this study. Clinicopathologic factors from both the primary tumor and the local recurrence were analyzed.

Results: The median interval to initial local recurrence was 16 months: 65% developed a local recurrence by 2 years and 90% by 4 years. Only four patients who presented with a low-grade primary tumor progressed to a high-grade local recurrence. Independent prognostic factors for disease-specific survival after local recurrence were a high histological grade (hazard ratio, 5.1; P = .0004), a large local recurrence tumor size (hazard ratio, 1.5; P = .0001), and a short local recurrence–free interval (hazard ratio, 1.6; P = .0001). Patients who developed a local recurrence >5 cm in ≤16 months (n = 44; 0 low grade) had a 4-year disease-specific survival of 18%, compared with 81% for patients who developed a local recurrence ≤5 cm in >16 months (n = 46; 11 low grade).

Conclusions: Histological grade, local recurrence size, and local recurrence–free interval are independently predictive of survival in patients with locally recurrent extremity STS. A large local recurrence that develops in a short interval indicates a biologically aggressive tumor with a high tumor-specific mortality. Patients who develop such recurrences are ideal subjects for systemic neoadjuvant therapy trials.

Key Words: Local recurrence • Extremity soft tissue sarcoma • Prognostic factors • Adjuvant therapy


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Although the ability to treat patients with locally recurrent disease is essential in many areas of surgical oncology, it is particularly important in the management of soft tissue sarcoma (STS). Despite improvements in imaging and surgical technique and the use of multimodality therapy, local recurrence remains a significant problem for patients with extremity STS. The local recurrence rate after treatment of primary extremity STS ranges from 10% to 15% in recently published series, and up to 30% of patients who present to university hospitals or cancer centers present with locally recurrent disease.1–11

The adverse prognostic factors for primary extremity STS have been well established by numerous studies. High histological grade, large size, and deep location have consistently proven to be predictive of decreased disease-specific survival.1–6,12,13 The ability to identify high-risk characteristics has played a significant role in improving the management of patients with this disease. Just as it has been important in patients with primary disease, it is also important to identify such prognostic factors for patients with locally recurrent disease. A number of studies have considered local recurrence in extremity STS, most of which have focused on whether local recurrence, in and of itself, is a prognostic variable associated with decreased survival.1,2,8–10,13–17 Very few studies have looked at the factors predictive of survival in patients with locally recurrent extremity STS, and these studies are limited by small numbers, short follow-up, and a mixture of initial presentation status.6–11,15,16–19 Besides not defining the interval between treatment of the primary tumor and presentation with local recurrence, most of these studies do not specify the tumor characteristics they examined: those of the primary or the local recurrence. Finally, no study has identified and compared both the primary and the local recurrent tumor characteristics.6–11,14–19 Thus, the factors predictive of survival in patients with locally recurrent extremity STS have not been well defined.

A study population of patients who developed a local recurrence while being followed up at the same institution that performed the primary operation was identified to achieve two objectives. These were (1) to identify and compare primary and local recurrence tumor characteristics and (2) to analyze factors predictive of post–local recurrence survival.


   METHODS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
A prospective database of adult patients (aged ≥16 years) with STS treated at Memorial Sloan-Kettering Cancer Center (MSKCC) was established in July 1982. From July 1982 to July 2002, 2009 patients underwent treatment for extremity STS. Of these, 1421 patients underwent surgical treatment for primary extremity STS. Two hundred twenty-eight of these patients developed a local recurrence. Patients who developed a distant recurrence before (n = 16) or simultaneous to (n = 5) the development of the local recurrence and who underwent nonoperative treatment (n = 4) or subtotal gross resection (n = 3) for the local recurrence were excluded from the analysis. In addition, all patients with the histopathology of desmoid (n = 18) and dermatofibrosarcoma protuberans (n = 3) were excluded. The remaining 179 patients who underwent surgery for primary extremity STS at MSKCC and subsequently developed a local recurrence represent the study population (Fig. 1Go).



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  		FIG. 1. MSKCC, 1982 to 2002. 1°, primary; STS, soft tissue sarcoma; MSKCC, Memorial Sloan-Kettering Cancer Center; DR, distant recurrence; LR, local recurrence; DFSP, dermatofibrosarcoma protuberans.

 
Patient and tumor characteristics were tested for their association with disease-specific survival. Patient variables included sex and age at diagnosis. Primary tumor characteristics included site, depth, histological subtype, histological grade, size, and microscopic margin status. Local recurrence tumor characteristics included depth, histological grade, size, microscopic margin status, and interval to local recurrence.

An upper extremity tumor was defined as a tumor at or distal to the shoulder. A lower extremity tumor was defined as a tumor at or distal to the groin or gluteal region. Depth was defined as either superficial or deep to the superficial investing muscular fascia. Tumor grade was classified as high or low according to established criteria, including degree of cellularity, differentiation, nuclear pleomorphism, and number of mitoses per high-power field.20 Tumor size was defined as the maximum diameter at pathologic analysis.

All patients underwent complete surgical resection or amputation of their primary tumor at MSKCC. Margin status was determined as part of the histopathologic assessment. Negative microscopic margins were defined as no tumor at the inked margin. Positive microscopic margins were defined as tumor at the inked margin. Local recurrence was defined as tumor recurrence at the site of previously treated tumor bed. All patients underwent complete resection or amputation of their local recurrence at MSKCC. Assessment of depth, grade, size, and margin status of the local recurrence was preformed in an identical manner to that for the primary tumor. The interval to local recurrence was measured from the date of the initial operation to the date of local recurrence.

Adjuvant therapy in the form of chemotherapy (CTX), external beam radiation, or brachytherapy was administered in many cases. These treatments or combinations of treatments were not prospectively or uniformly administered and thus are recorded but not included in the statistical analysis.

The tumor depth, grade, and margin status and the surgical procedure of the primary tumor and the local recurrence were compared by using McNemar’s test. The sizes of the primary tumor and the local recurrence were compared by using the signed rank test. Spearman’s rank correlation between the size of the local recurrence and the interval to local recurrence was calculated. Death caused by disease was treated as the end point for disease-specific survival. The disease-specific survival duration was measured from the date of local recurrence to the date of death due to disease or to the last follow-up. Survival curves were generated with the Kaplan-Meier method. Univariate analysis was performed with the log-rank test for categorical variables and the Cox proportional hazards model for continuous variables. Two- and 4-year survival estimates are presented, along with 95% confidence intervals in parentheses. Variables significant at the .2 level were entered into a multivariate analysis, which was performed by using the Cox proportional hazards model. Hazard ratios and corresponding 95% confidence intervals are presented for independent prognostic variables.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Patient and Tumor Characteristics
The clinicopathologic characteristics of the 179 adult patients with locally recurrent extremity STS are listed in Table 1Go. The median age was 58 years (range, 16–92 years). There were 105 (59%) males and 74 (41%) females. Most patients had lower extremity (62%; n = 111) tumors. Malignant fibrous histiocytoma (MFH; 35%; n = 62) and liposarcoma (26%; n = 46) were the two most common histologies. Seventy-nine percent (n = 142) of the primary tumors were deep, and 90% of the local recurrences were deep (P < .0001). Seventy-eight percent (n = 139) of the primary tumors were high grade, and 22% (n = 40) were low grade. Only four patients who presented with low-grade primary tumors (4 of 40; 10%) progressed to a high-grade local recurrence. Therefore, 80% (n = 143) of the local recurrences were high grade, and 20% (n = 36) were low grade (P = .13). The histologies of these four tumors were MFH, liposarcoma, fibrosarcoma, and extraskeletal chondrosarcoma.


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  		TABLE 1. Clinicopathologic characteristics of the 179 patients with locally recurrent extremity soft tissue sarcoma
 
Twenty-six percent (n = 47) of the patients had a microscopically positive margin after resection of the primary tumor, and 27% (n = 49) had a microscopically positive margin after resection of the local recurrence (P = .90). The median primary tumor size was 7 cm (range, 1–38 cm), and the median tumor size at local recurrence was 5 cm (range, .5–15.0 cm; P = .0001). Sixty-five percent of the patients developed the local recurrence by 2 years and 90% by 4 years, and the median interval to local recurrence was 16 months (range, 3–129 months; Fig. 2Go). There were 45 small (≤5 cm) and 44 large (>5 cm) local recurrences that developed within a short interval (≤16 months). Similarly, 46 small and 44 large local recurrences developed within a longer interval (>16 months). The rank correlation between the size of the local recurrence and the interval to local recurrence was (–.01 and was not significantly different from 0 (P = .88).



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  		FIG 2. Time to first local recurrence (LR).

 
Treatment
Ninety-eight percent (n = 175) of the patients underwent limb-sparing surgery for their primary tumor, and only 2% (n = 4) of the patients required amputation. By comparison, 89% (n = 159) underwent limb-sparing surgery for the local recurrence, and 11% (n = 20) required amputation (Table 1Go). Sixty-five percent (n = 117) of the patients were treated with radiotherapy (XRT), and 35% (n = 62) received no XRT. Seventy-nine (44%) underwent treatment with XRT before and 38 (21%) after the development of their local recurrence. Sixty of the patients (33%) were treated with adjuvant CTX, and 119 (67%) received no CTX. Forty (22%) underwent treatment with CTX before the development of their local recurrence, and 20 (11%) underwent treatment with CTX after the development of their local recurrence. Forty-six (26%) received both XRT and CTX at some point over the course of their treatment.

Disease-Specific Survival
With a median follow-up of 49 months (range, 1–208 months) for surviving patients, the disease-specific survival was 68% (range, 60%–75%) at 2 years and was 55% (range, 47%–63%) at 4 years (Fig. 3Go). The 4-year disease-specific survival for patients with high-grade primary tumors was 46% (range, 37%–55%), compared with 87% (range, 74%–99%) for patients with low-grade primary tumors (Fig. 4Go). Six patients (15%) out of 40 with low-grade primary tumors died of disease. The histological subtypes of these patients were myxoid liposarcoma (n = 3), MFH (n = 2), and extraskeletal chondrosarcoma (n = 1). Only one of these six patients had a low-grade primary tumor (MFH) that progressed to a high-grade local recurrence.



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  		FIG 3. Disease-specific survival. LR, local recurrence.

 


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  		FIG 4. Disease-specific survival by primary tumor grade. LR, local recurrence.

 
Univariate analysis of all clinicopathologic variables prognostic for disease-specific survival revealed that older age, a deep primary tumor, leiomyosarcoma/malignant peripheral nerve sheath tumor histology, high histological grade (primary and local recurrence), large primary tumor size, large local recurrence tumor size, and a short local recurrence–free interval were all associated with decreased disease-specific survival (Table 2Go). By multivariate analysis, high histological grade (primary and local recurrence), large local recurrence tumor size, and a short local recurrence–free interval were found to be independently associated with decreased disease-specific survival (Table 2Go). Patients who developed a local recurrence >5 cm in ≤16 months (n = 44) had a 4-year disease-specific survival of 18% (range, 5%–31%). All 44 of these patients had high-grade tumors. By comparison, patients who developed a local recurrence ≤5 cm in >16 months (n = 46) had a 4-year disease-specific survival of 81% (range, 67%–94%). Thirty-five of these patients had high-grade tumors, and 11 had low-grade tumors. The remaining patients who developed a local recurrence ≤5 cm in ≤16 months (n = 45; 12 low grade) and >5 cm in >16 months (n = 44; 13 low grade) had 4-year disease-specific survivals of 57% (range, 40%–73%) and 63% (range, 47%–80%), respectively (Fig. 5Go).


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  		TABLE 2. Analysis of clinicopathologic characteristics for disease-specific survival (n = 179)
 


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  		FIG 5. Disease-specific survival (DSS) by local recurrence (LR)-free interval and size of LR.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Accurate analysis of locally recurrent extremity STS is predicated on the population of patients studied. It is important to distinguish between patients who present with locally recurrent disease after having undergone treatment for the primary tumor at another institution versus at the same institution. Patients who present with locally recurrent disease can have a long interval between initial treatment and presentation with locally recurrent disease. A recent publication by Eilber et al.6 found the mean interval between treatment of the primary tumor at another institution and presentation to the University of California–Los Angeles with locally recurrent disease to be 30 months. In addition, 40% of the patients with primary disease that subsequently locally recurred died within 2 years of the local recurrence. This suggests that patients who present initially with locally recurrent disease tend to be a highly selected population, particularly if their interval to local recurrence is long.6 Further difficulties in drawing conclusions from such a population include an unknown extent of initial surgery and limited information about the primary tumor’s pathologic characteristics.

The ideal population of patients to study is one that has developed a local recurrence while being followed up at the same institution that performed the primary operation. Unfortunately, the studies on locally recurrent extremity STS have analyzed a selected population of either patients who presented initially with locally recurrent disease or patients with a mixture of initial presentation status.7–11,15,16,18 In either instance, these studies do not define the interval between treatment of the primary tumor and presentation with locally recurrent disease or which tumor characteristics they examined. Two questions arise that are fundamental to the management of these patients. What are the differences between the primary tumor and local recurrence tumor characteristics? Which tumor characteristics are predictive of survival: those of the primary, the local recurrence, or both?

To address these questions, data of 179 patients with extremity STS who underwent complete surgical resection of both the primary tumor and subsequent local recurrence at MSKCC were analyzed. Patient and tumor characteristics for these 179 patients were similar to those in large series of patients with primary extremity STS, and no histology was disproportionately represented1–7 (Table 1Go). It is interesting to note that there was not a significant difference between the grade of the primary tumor and the grade of the local recurrence. Only four patients who presented with a low-grade primary tumor progressed to a high-grade local recurrence, and this progression occurred in four different histologies. In addition, there was not a significant difference between the number of patients with a microscopically positive margin after resection of the primary tumor and resection of the local recurrence. There was, however, a significant difference between the depth and size of the primary tumor and the depth and size of the local recurrence. There were 161 (90%) deep tumors at local recurrence, compared with 142 (72%) deep primary tumors (P < .0001). The median tumor size at local recurrence was 5 cm, compared with a median primary tumor size of 7 cm (P < .0001).

The median interval to local recurrence was 16 months, and 65% of patients developed a local recurrence by 2 years and 90% by 4 years (Fig. 1Go). Further analysis of the possible relationship between the interval to local recurrence and the size of the local recurrence was performed. This was specifically undertaken to determine whether the smaller local recurrences were discovered early and the larger local recurrences were discovered late. The rank correlation between the size of the local recurrence and the interval to local recurrence was –0.01 and was not significantly different from 0. No correlation was thus found between the size of the local recurrence and the interval to local recurrence.

Careful follow-up of patients for the first 4 years after resection of their primary extremity sarcoma is clearly warranted, because 90% of the local recurrences developed within this time period. When to use cross-sectional imaging of the extremity in addition to physical examination and whether discovering a local recurrence at a smaller size in a shorter interval would affect the limb salvage rate or the survival of these patients are unclear.18,21,22 Because the cost and quality of such imaging continues to improve, the questions surrounding optimal follow-up remain an excellent area for prospective investigation.

Only four (2%) patients required amputation for their primary tumor, and this number increased to 20 (11%) for the local recurrence. Despite an increase in the number of patients requiring amputation, the vast majority (89%) of patients with locally recurrent disease were able to undergo limb-sparing surgery.6,23–26 Sixty-five percent of the patients were treated with XRT and 33% with CTX. Although 131 (73%) of the patients received 1 or more forms of these adjuvant therapies, the treatments were not prospectively or uniformly administered, thus making it difficult to draw any treatment-related conclusions.27–29

With a median follow-up of >4 years for surviving patients, the disease-specific survival for all 179 patients was 68% at 2 years and 55% at 4 years (Fig. 3Go). The fact that 45% of all patients died of disease within 4 years of developing a local recurrence demonstrates the high-risk nature of this disease. As might be anticipated, patients with high-grade tumors had a significantly worse tumor-specific mortality than patients with low-grade tumors (Fig. 4Go). It is interesting to note that of the six (15%) patients with low-grade primary tumors who died of disease, three (7.5%) had myxoid liposarcomas. This suggests that low-grade tumors of this histological subtype warrant particular attention.

Analysis of the patient and tumor characteristics associated with disease-specific survival revealed that a high histological grade (primary and local recurrence), a large local recurrence tumor size, and a short local recurrence–free interval were all independently associated with decreased disease-specific survival. Surprisingly, primary tumor size was not significant on multivariate analysis. This—in conjunction with the fact that tumor grade remained essentially unchanged—allows for prompt treatment planning to occur at presentation with locally recurrent disease. Specifically, the surgeon needs the date of the primary operation, original pathology slides to confirm histology and grade, and cross-sectional imaging of the extremity to assess the local recurrence size.

Although the development of a local recurrence can be frustrating and clinically challenging for both the patient and the surgeon, it does offer a unique glimpse at the biology of this disease. Because the time it takes for the tumor to grow to a pathologically defined size is known, the growth rate can be assessed. These growth rate characteristics are predictive of disease-specific survival and represent an expression of tumor aggressiveness that is independent of histological grade. The profound significance of these characteristics is graphically illustrated in Fig. 5Go. Patients who developed a local recurrence >5 cm in ≤16 months had a 4-year disease-specific survival of 18% (range, 5%–31%). In comparison, patients who developed a local recurrence <5 cm in >16 months had a 4-year disease-specific survival of 81% (range, 67%–94%).

In summary, 65% of the patients with locally recurrent extremity STS developed the local recurrence within 2 years of the primary surgery. No significant difference was found between the grade of the primary tumor and the grade of the local recurrence. The median tumor size of the local recurrence was significantly smaller than the median tumor size of the primary tumor. Histological grade, local recurrence size, and local recurrence–free interval are independently predictive of survival in patients with locally recurrent extremity STS. A large local recurrence that develops in a short interval indicates a biologically aggressive tumor with a high tumor-specific mortality. Patients who develop such recurrences are ideal subjects for systemic neoadjuvant therapy trials.


   ACKNOWLEDGMENTS
 
Supported by National Institutes of Health Program Project Grant P01CA47179 (M.F.B. and S.S.) and a Kristen Ann Carr Fellowship (F.C.E.).

Received for publication March 19, 2004. Accepted for publication November 19, 2004.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Brennan MF. The enigma of local recurrence. Ann Surg Oncol 1997;4:1–12.[Abstract]
  2. Pisters PWT, Leung DHY, Woodruff J, Shi M, Brennan MF. Analysis of prognostic factors in 1,041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 1996;14:1679–1689.[Abstract/Free Full Text]
  3. Coindre J, Terrier P, Bui NB, 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 1996;14:869–77.[Abstract/Free Full Text]
  4. Lewis JJ, Leung D, Casper ES, Woodruff J, Hajdu SI, Brennan MF. Multifactorial analysis of long-term follow-up (more than 5 years) of primary extremity sarcoma. Arch Surg 1999;134: 190–4.[Abstract/Free Full Text]
  5. Eilber FC, Rosen G, Eckardt J, et al. Treatment induced pathologic necrosis: a predictor of local recurrence and survival in patients receiving neoadjuvant therapy for high grade extremity soft tissue sarcomas. J Clin Oncol 2001;19:3203–9.[Abstract/Free Full Text]
  6. Eilber FC, Rosen G, Nelson SD, et al. High grade extremity soft tissue sarcomas. Factors predictive of local recurrence and its effect on morbidity and mortality. Ann Surg 2003;237:218–26.[CrossRef][Medline]
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  12. Gaynor JJ, Tan CC, Casper ES, et al. Refinement of clinicopathologic staging for localized soft tissue sarcoma of the extremity: a study of 423 adults. J Clin Oncol 1992;10:1317–29.[Abstract/Free Full Text]
  13. Singer S, Corson JM, Gonin R, Labow B, Eberlein TJ Prognostic factors predictive of survival and local recurrence for extremity soft tissue sarcoma. Ann Surg 1994;219:165–73.[Medline]
  14. Giuliano AE, Eilber FR, Morton DL The management of locally recurrent soft-tissue sarcoma. Ann Surg 1982;196:87–91.[Medline]
  15. Karakousis CP, Proimakis C, Rao U, Velez AF, Driscoll DL Local recurrence and survival in soft-tissue sarcomas. Ann Surg Oncol 1996;3:255–60.[Abstract]
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  17. Lewis JJ, Leung D, Heslin M, Woodruff JM, Brennan MF Association of local recurrence with subsequent survival in extremity soft tissue sarcoma. J Clin Oncol 1997;15:646–52.[Abstract/Free Full Text]
  18. Midis GP, Pollock RE, Chen NP, et al. Locally recurrent soft tissue sarcoma of the extremity. Surgery 1998;123:666–71.[Medline]
  19. Stojadinovic A, Yeh A, Brennan MF Completely resected recurrent soft tissue sarcoma: primary anatomic site governs outcome. J Am Coll Surg 2002;194:436–47.[CrossRef][Medline]
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  26. Stojadinovic A, Jaques DP, Leung DH, Healey JH, Brennan MF Amputation for recurrent soft tissue sarcoma of the extremity: indications and outcome. Ann Surg Oncol 2001;8:509–18.[Abstract/Free Full Text]
  27. Pisters PW, Harrison LB, Leung DH, Woodruff JM, Casper ES, Brennan MF Long-term results of a prospective randomized trial of adjuvant brachytherapy in soft tissue sarcoma. J Clin Oncol 1996;14:859–68.[Abstract/Free Full Text]
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