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© 1999 American Society for Clinical Oncology Long-Term Outcome of Patients With American Joint Committee on Cancer Stage IIB Extremity Soft Tissue SarcomasFrom the Sarcoma Center at The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Peter W.T. Pisters, MD, Department of Surgical Oncology, Box 106, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030-4195; email ppisters{at}mdanderson.org
PURPOSE: It has been suggested that patients with small (< 5 cm), high-grade extremity soft tissue sarcomas (STS) have an excellent overall prognosis and, consequently, may not require adjuvant therapies. PATIENTS AND METHODS: A comprehensive review of all patients with extremity STS treated at a tertiary care cancer hospital over a 9-year period (January 1984 to December 1992) was performed. Prognostic factors, treatment data, and long-term outcome were evaluated in the subset of 111 patients with American Joint Committee on Cancer stage IIB (G3/4, T1a/b) disease. RESULTS: The median tumor size was 3.0 cm (range, 0.6 to 4.9 cm), and 55 tumors (50%) were deep in location. All patients underwent surgical resection; 68 (61%) received pre- or postoperative radiotherapy, and 32 (29%) received doxorubicin-based chemotherapy. The median follow-up was 76 months. Forty patients (36%) experienced 59 recurrences. First recurrences occurred at local, regional, and distant sites in 21, five, and 14 patients, respectively. The 5-year actuarial local recurrence-free, distant recurrence-free, disease-free, and overall survival rates were 82%, 83%, 68%, and 83%, respectively. The presence of a microscopically positive surgical margin was an independent adverse prognostic factor for both local recurrence (relative risk [RR] = 3.75; 95% confidence interval [CI], 1.25 to 11.25; P = .02) and disease-free survival (RR = 2.57; 95% CI, 1.33 to 4.98; P = .005). CONCLUSION: Event-free outcome for this subset of patients with high-grade STS does not seem as favorable as previously reported by other investigators. Patients who undergo maximal surgical resection with microscopically positive margins represent a subset of T1 STS patients who warrant consideration for adjuvant therapies.
OVER THE PAST DECADE, several studies evaluating prognostic factors in patients with soft tissue sarcoma (STS) have been reported.1-3 These studies have uniformly identified tumor size as a prognostic factor for the subsequent development of distant metastatic disease and tumor-related death. Although size is a continuous variable, tumor size has commonly been dichotomized at 5 cm, with most studies evaluating the prognostic significance of sarcomas 5 cm or larger (T2) as compared with lesions less than 5 cm (T1). The relative risk for sarcoma-related death reported for T2 tumor size (v T1) in these prognostic factor studies has ranged between 2.1 and 3.1, demonstrating the substantial adverse risk imposed by larger tumor size.1-3 By inference from these studies and acquired clinical experience, it is generally accepted that, with the possible exception of specific types of small-cell sarcomas, patients with T1 sarcomas have an excellent overall prognosis. One large study has been reported outlining the prognosis of patients with T1 STS.4 In a study of 176 patients with small extremity STS treated at Memorial Sloan-Kettering Cancer Center (MSKCC), disease-free and overall survival rates were 90% and 95%, respectively, with a median follow-up of 42 months. This ostensibly excellent outcome seemed to be similar (by univariate analysis) regardless of tumor grade; patients with low- and high-grade lesions had 5-year overall survival rates of 100% and 91% (P = .15), respectively.4 Nevertheless, clinical experience and a recent report suggest that late recurrence (> 5 years after treatment) is not a rare event for patients with STS.5 In this respect, there have been no studies of stage-specific long-term outcome for patients with T1 extremity STS. Thus, the present study sought to define the long-term outcome for patients with American Joint Committee on Cancer (AJCC) stage IIB (G3/4, T1a/b) extremity STS.
From January 1, 1984, to December 31, 1992, 1,041 patients with extremity STS were evaluated at The University of Texas M.D. Anderson Cancer Center. A comprehensive retrospective review of the medical records of the subset of 711 adult (age > 16 years) patients, who had received the majority of their treatment and follow-up at M.D. Anderson, was performed. Using the available clinical and pathologic data, this cohort of patients was retrospectively staged by two of the authors (P.T.W.P., N.P.C.) according to the AJCC staging system for extremity STS.6 Details of radiologic assessment, clinicopathologic prognostic factors, treatment, and long-term follow-up were recorded for each patient. Of the 711 patients treated primarily at M.D. Anderson, 111 adult patients (16%) presented with high-grade, T1a or T1b (stage IIB) disease and form the basis of this report. The following definitions were used: 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 previously treated for an extremity STS. 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 in the groin or leg. Axillary and iliac fossa tumors were excluded. Tumor size was defined as the maximum dimension obtained during three-dimensional (craniocaudal, transverse, and anteroposterior) assessment of the lesion using cross-sectional imaging performed immediately before referral or on initial evaluation at M.D. Anderson. For patients referred to M.D. Anderson after excisional biopsy, the pathologic size of the resected tumor was used as the tumor size. All patients in this study had T1 (< 5 cm) lesions that were determined to be high-grade (AJCC grade 3 or 4) based on the degree of cellularity, degree of differentiation, number of mitoses per high-power field, amount of stromal necrosis, and degree of vascularity. The anatomic depth of tumors was evaluated relative to the investing fascia of the extremity, with tumors being characterized as either superficial (T1a) or deep (T1b). A microscopically positive surgical margin was defined as tumor present at the inked margin of the specimen. Summary statistics were obtained using established methods. Differences in proportions were assessed using the Fisher's exact test. Overall survival was defined as the time from the date of initiation of therapy at M.D. Anderson to death from any cause. Overall survival and disease-free survival curves were estimated by the Kaplan-Meier method,7 and the standard errors were calculated based on Greenwood's formula.8 The log-rank test and Cox proportional hazards regression model were used to test for the significance of differences between disease-free survival curves and between overall survival curves. "Local" and "regional/distant" were considered two competing sites of first recurrence. In the presence of dependent competing risks, the Kaplan-Meier cause-specific curve consistently overestimates the probabilities of failure from a specific cause (site).9 Therefore, for each of the competing sites, cause-specific cumulative incidence functions were estimated, and differences between groups were tested.10 All P values were two-sided and were not adjusted for multiple comparisons. A P value of less than .05 was considered to be statistically significant.
Patients and Prognostic Factors Table 1 lists the distribution of clinicopathologic factors in the 111 patients with AJCC stage IIB disease. The median age of the study population at presentation to M.D. Anderson was 40 years (range, 16 to 82 years). There were 59 men (53%) and 52 women (47%). The majority of patients (80%) presented with localized primary sarcomas. The anatomic site was relatively evenly distributed between upper (42%) and lower (58%) extremities; similarly, 50% presented with superficial tumors (T1a) and 50% with deep tumors (T1b). The median tumor size was 3.0 cm (range, 0.6 to 4.9 cm). The most common histologic subtype was malignant fibrous histiocytoma (41%). The majority of patients (77%) underwent resection with microscopically negative surgical margins.
Treatment Twenty-six patients (23%) underwent initial surgery at M.D. Anderson. Surgical excision was performed at outside institutions before referral in 85 patients (77%). Further surgery at M.D. Anderson, in an effort to achieve wider and/or microscopically negative surgical margins, was performed in 70 of these patients. Fifteen patients who had undergone prereferral surgical resection did not undergo further surgery at M.D. Anderson, either because microscopic margins were believed to be adequate or because functionally significant neurovascular structures in proximity to the original tumor or tumor bed precluded further meaningful attempts at achieving wider margins without amputation or loss of major extremity function. Most patients (n = 101) were treated by limb-sparing surgery; 10 patients required amputation, all for tumors of the hands or feet. A microscopically positive surgical margin was present after definitive surgery in 22 cases (20%). Among the 22 patients with microscopically positive surgical margins, 10 were patients with distal lesions located in the hand, foot, or ankle region. Seven of the 22 patients had proximal lesions that were located in proximity to functionally significant neurovascular structures or bone; in these patients, further surgery was believed likely to result in substantial compromise of extremity function. The other five patients with microscopically positive surgical margins refused recommended re-excision and were treated with postoperative radiotherapy instead. Surgery combined with external-beam radiotherapy was used in 68 patients; 18 of these patients (26%) received preoperative radiotherapy (median dose, 50 Gy; range, 30 to 70 Gy), and 50 (74%) were treated with postoperative radiotherapy (median dose, 65 Gy; range, 50 to 70 Gy). Doxorubicin-based pre- (n = 9), post- (n = 9), or perioperative (n = 14) chemotherapy was used in 32 patients (median doxorubicin starting dose, 60 mg/m2; range, 50 to 90 mg/m2) for a median of four cycles (range, one to eight cycles).
Recurrences
Local recurrence.
Local recurrence-free survival was also evaluated as a function of treatment. Among the 43 patients treated by surgery without radiotherapy, eight first local recurrences were observed as compared with 13 first local recurrences in the 68 patients treated by surgery plus radiotherapy. The 5-year, actuarial, local recurrence-free survival rate in patients treated by surgery without radiotherapy was 83% (95% CI, 71% to 95%) as compared with 82% (95% CI, 72% to 92%) for patients treated with surgery plus radiotherapy (log-rank P = .87).
Distant recurrence.
Late recurrence.
Disease-Free Survival
Overall Survival
The presence of any recurrence was the most significant factor associated with a reduced overall survival rate (P < .0001). The type of first recurrence also had a significant impact on overall survival. Of the 71 patients who had no recurrence during the follow-up period, five (7%) died, all of other causes. Of the 21 patients who experienced local recurrence first, 10 (48%) died (eight of advanced sarcoma and two of other causes). Of the 19 patients who had a regional or distant recurrence first, 14 (74%) died (13 of advanced sarcoma and one of other causes). The 5-year, actuarial, overall survival rate was 97% (95% CI, 93% to 100%) for those who had no recurrence, 70% (95% CI, 53% to 93%) for those who had a local recurrence first, and 48% (95% CI, 29% to 79%) for those who had a regional or distant recurrence first.
Survival and Presentation Recurrence of any type was seen in 30 of 89 patients presenting with primary disease and 11 of 22 patients presenting with locally recurrent disease. The 5-year, actuarial, disease-free survival rates were 73% (95% CI, 64% to 83%) in patients with primary disease and 50% (95% CI, 32% to 76%) in patients presenting with locally recurrent sarcoma (P = .20). Twenty-two of 89 patients presenting with primary sarcomas died during the follow-up period, as compared with seven of 22 patients presenting with locally recurrent disease. The 5-year, actuarial, overall survival rates were 86% (95% CI, 79% to 94%) in patients with primary disease and 72% (95% CI, 55% to 94%) in patients presenting with locally recurrent sarcoma (P = .65).
We report long-term outcome for patients with stage IIB extremity STS treated at a tertiary care cancer center. Our data suggest that the outcome for these patients, although generally favorable, is not as favorable as previously reported.4 We did not observe the 90% or greater disease-free and overall survival rates that were seen by Geer et al4 in their report on T1 extremity STS patients treated at MSKCC. The reasons for this discrepancy are likely multifactorial and include the longer follow-up in the present report (median 76 months v 42 months at MSKCC), the stage-specific nature of this report (which included only patients with high-grade lesions as compared with the prior report, which included all grades), the inclusion of patients with locally recurrent disease in the present report, and perhaps differences in the referral-based populations seen at these institutions. Even when restricting the comparison to patients with primary high-grade lesions, the 89 such patients in the present report had a 5-year overall survival rate of 86% (95% CI, 79% to 94%) as compared with 91% (CIs not reported) for the 114 patients with high-grade lesions reported by Geer et al.4 The phenomenon of late recurrence (> 5 years posttreatment) of STS has been anecdotally observed and recently reported.5 Unlike other malignancies, for which 5 years is often used as a benchmark for the patient and physician to define a "cure," patients with STS who remain free of disease at 5 years have at least a 10% chance of experiencing recurrence in the subsequent 5 years of follow-up.5 Indeed, in the present study, six (15%) of 40 patients experienced their first recurrence after 5 years (three local and three distant recurrences). These findings underscore the importance of long-term follow-up of patients treated for STS, even for patients who seem to have fairly low-risk, early-stage tumors. Until more data are available, it seems that all STS patients should be observed for at least 10 years after treatment. At the time of initial presentation, it is difficult to identify the one out of five patients with a small high-grade sarcoma who will die of their disease. Although the present report suggests that traditional clinicopathologic adverse prognostic factors, such as larger T1 tumor size, deep anatomic location, and microscopically positive surgical margin, may help to identify patients at higher risk for recurrence, only a microscopically positive surgical margin was of independent prognostic significance in the regression analysis for disease-free survival (RR = 2.57; 95% CI, 1.33 to 4.98; P = .005). We believe that the absence of a statistically significant relationship between microscopic surgical margin status and overall survival in the current report is a function of the relatively small number of patients who died of sarcoma (n = 22). The discriminative capacity of a multivariate analysis designed to identify prognostic factors for survival is a function of the number of patients who experienced the end point (ie, death). Thus, our ability to identify significant prognostic factors for survival is considerably less than would be the case in a similar analysis in which a larger number of patients experienced sarcoma-related death. Indeed, a statistically significant relationship between microscopically positive surgical margins and overall survival has been demonstrated by other investigators using data sets with a greater number of patients who experienced sarcoma-related mortality.3,11 Thus, if one considers the statistically significant relationship between margin status and disease-free survival found in our study in the context of the existing literature, it is likely that stage IIB extremity sarcoma patients with microscopically positive surgical margins are at higher risk for tumor-related death than are patients with microscopically negative surgical margins. The etiology of a microscopically positive margin after ostensibly adequate sarcoma surgery may be multifactorial. Contributing factors may include the anatomic relationship of the tumor to functionally important neurovascular structures, the nature and extent of prior local therapies including surgery and/or radiotherapy that individually and collectively act to limit current surgical treatment, and the infiltrating nature of some types of STS. Given the adverse prognostic significance of a microscopically positive margin in this study and prior reports,3,11 it is becoming increasingly apparent that, in the presence of satisfactory gross margins at surgery, a microscopically positive surgical margin may be a reflection more of aggressive tumor biology than of inadequate local therapy. The optimal multidisciplinary approach for patients with stage IIB sarcoma who undergo surgical resection with ostensibly satisfactory gross margins but are found to have microscopically positive surgical margins on final pathologic analysis is not clear. Certainly, the ideal management option for a patient with a sarcoma excised with positive margins is referral to a center specializing in sarcoma treatment for multidisciplinary evaluation of the potential efficacy of reoperative surgery (to achieve wider and hopefully microscopically negative margins) and/or radiotherapy. This seems important given the generally worse outcome for patients with microscopically positive surgical margins3,11 and the improved outcome associated with treatment of sarcoma patients in centers with a multidisciplinary sarcoma team.12,13 Patients with a microscopically positive surgical margin after ostensibly adequate surgery who, in the judgment of a surgical oncologist with expertise in soft tissue tumors, cannot undergo further limb-sparing surgery (usually because of anticipated loss of functionally significant neurovascular structures) should be treated with postoperative radiotherapy given the local control benefit of adjuvant radiotherapy.14,15 The possible role for systemic therapy in the high-risk subset of stage IIB patients is unclear. In the present report, the 5-year, actuarial, disease-free survival rate for stage IIB patients with microscopically positive resection margins treated in a multidisciplinary sarcoma unit was 43%, as compared with 75% (P = .0003) for those with a negative surgical margin. This 43% rate is comparable to the approximately 50% distant recurrence-free survival rate among patients with T2 high-grade lesions, patients who are commonly offered pre- or postoperative chemotherapy.16 These data and the generally worse outcome reported for patients with microscopically positive surgical margins3,11 suggest that stage IIB patients with a microscopically positive surgical margin after maximal local therapy could be included in the subset of patients with high-grade sarcoma considered for postoperative systemic therapy. The absolute survival advantage of postoperative chemotherapy remains unproven, but such treatment may improve local control.17 Independent of a defined survival advantage, to the extent that local control may be improved with postoperative chemotherapy, it is possible that such chemotherapy may allow some high-risk patients who have already been treated with maximal limb-salvage surgery to avoid amputation as a salvage approach for locally recurrent disease. Clinical experience4 and increased appreciation of the long-term adverse effects of bimodality therapy (surgery plus radiation) on extremity function18,19 have led to interest in treating some sarcoma patients with surgery without radiotherapy. Indeed, an evolving body of literature suggests that selected patients with T1 sarcoma may be satisfactorily treated by surgery alone.20-22 These reports have generally used specific selection criteria (usually a grossly and microscopically negative surgical margin) to identify subsets of patients who have been treated by surgery alone. With careful patient selection, local recurrence rates seem to be in the 4% to 10% range,20-23 suggesting that not all patients with T1 STS require radiotherapy. The present report does not allow specific comment on the optimal treatment for patients with T1 high-grade sarcomas. Indeed, in the analysis, there seemed to be no specific association between treatment-related factors and outcome. However, this type of analysis is limited by the retrospective nature of the data and the fact that specific treatment approaches (unimodality v multimodality) were not randomly assigned but rather applied at the time of presentation based on the constellation of prognostic factors. Therefore, these data do not allow us to clearly define subsets of T1 sarcoma patients who can be treated by surgery alone. This can be performed only within the context of prospective trials. Our current approach to patients with T1 extremity sarcomas located in a favorable anatomic region (where satisfactory wide surgical margins can be obtained) is to treat them with surgical resection and use radiotherapy selectively (for patients with microscopically positive surgical margins).24 In summary, it seems that the long-term outcome for patients with T1 high-grade sarcoma may not be as favorable as previously reported. Indeed, subsets of stage IIB sarcoma patients seem to have a risk for recurrence that approaches that seen with traditional high-risk extremity sarcoma (high-grade histology, T2 size, and/or deep location). This report also emphasizes the importance of long-term follow-up in this disease, as a substantial number of patients will experience recurrence more than 5 years after treatment. Future research should focus on identifying molecular prognostic factors that may better define the subset of high-risk T1 tumors. Prospective clinical trials are needed to evaluate which groups of patients with T1 lesions require combined-modality therapy and which subsets of patients can be safely spared the financial expense and the risks for short- and long-term toxicities associated with combined-modality treatment.
Supported by American Cancer Society Development Award ACS 96-98 (P.W.T.P.). We thank Vivian Z. Garcia and Melissa Burkett for their assistance in the preparation of the manuscript.
Presented in part at the Annual Meeting of the Society of Surgical Oncology, San Diego, CA, March 1998.
1. 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 10:1317-1329, 1992
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Coindre JM, 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 14:869-877, 1996
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Pisters PWT, Leung DHY, Woodruff J, et al: Analysis of prognostic factors in 1041 patients with localized soft tissue sarcomas of the extremities. J Clin Oncol 14:1679-1689, 1996
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Lewis JJ, Leung DHY, Casper ES, et al: Multifactorial analysis of long-term follow-up (more than 5 years) of primary extremity sarcoma. Arch Surg 134:190-194, 1999 6. American Joint Committee on Cancer: Soft tissue sarcoma, in Fleming ID, Cooper JS, Henson DE, et al (eds): American Joint Committee on Cancer Staging Manual (ed 5). Philadelphia, PA, Lippincott-Raven, 1997, pp 149-156 7. Kaplan E, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457-481, 1958 8. Greenwood M: The natural duration of cancer. Rep Public Health Med Subj 33:1-26, 1926 9. Gelman R, Gelber RD, Henderson IC, et al: Improved methodology for analyzing local and distant recurrence. J Clin Oncol 8:548-555, 1990[Abstract] 10. Gray RJ: A class of K-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141-1154, 1988
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Heslin MJ, Woodruff J, Brennan MF: Prognostic significance of a positive microscopic margin in high-risk extremity soft tissue sarcoma: Implications for management. J Clin Oncol 14:473-478, 1996 12. Gustafson P, Dreinhofer KE, Rydholm A: Soft tissue sarcoma should be treated at a tumor center: A comparison of quality of surgery in 375 patients. Acta Orthop Scand 65:47-50, 1994[Medline] 13. Clasby R, Tilling K, Smith MA, et al: Variable management of soft tissue sarcoma: Regional audit with implications for specialist care. Br J Surg 84:1692-1696, 1997[Medline]
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Yang JC, Chang AE, Baker AR, et al: A 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
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Pisters PWT, Harrison LB, Leung DHY, 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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Pisters PWT, Patel SR, Varma DGK, et al: Preoperative chemotherapy for stage IIB extremity soft tissue sarcoma: Long-term results from a single institution. J Clin Oncol 15:3481-3487, 1997 17. Tierney JF: Adjuvant chemotherapy for localised resectable soft-tissue sarcoma of adults: Meta-analysis of individual data. Lancet 350:1647-1654, 1997[Medline] 18. Stinson SF, Delaney TF, Greenberg J, et al: Acute and long-term effects on limb function of combined modality limb sparing therapy for extremity soft tissue sarcoma. Int J Radiat Oncol Biol Phys 21:1493-1499, 1991[Medline] 19. Chang AE, Steinberg SM, Culnane M, et al: Functional and psychosocial effects of multimodality limb-sparing therapy in patients with soft tissue sarcomas. J Clin Oncol 7:1217-1228, 1989[Abstract] 20. Healey B, Corson JM, Demetri GD, et al: Surgery alone may be adequate treatment for select stage IA-IIIA soft tissue sarcomas. Proc Am Soc Clin Oncol 14:517, 1995 (abstr A1697) 21. 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] 22. Karakousis CP, Proimakis C, Walsh DL: Primary soft tissue sarcoma of the extremities in adults. Br J Surg 82:1208-1212, 1995[Medline] 23. Pisters PWT: Combined modality treatment of extremity soft tissue sarcomas. Ann Surg Oncol 5:464-472, 1998[Abstract] 24. 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) Submitted December 15, 1998; accepted April 27, 1999.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
