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© 2002 American Society for Clinical Oncology Primary Adult Soft Tissue Sarcoma: Time-Dependent Influence of Prognostic VariablesByFrom the Departments of Surgery and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY. Address reprint requests to Murray F. Brennan, MD, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10021; email: brennanm{at}mskcc.org
PURPOSE: To define prognostic factors for postrelapse survival and their time-dependent influence for adult soft tissue sarcoma (STS). PATIENTS AND METHODS: We analyzed 2,123 patients with completely resected localized primary STS treated from 1982 to 1999. Variables studied included tumor site, size, depth, grade, and resection margin but not treatment other than resection. Landmark time frames were used to assess the influence of disease-free interval (DFI) on disease-specific survival (DSS). DSS was estimated with the Kaplan-Meier method. Univariate and multivariate analyses were performed using log-rank test and the Cox proportional hazards regression model. Time-dependent stepwise regression analysis evaluated the time-dependent influence of each variable.
RESULTS: Two thirds of recurrences developed within 2 years of initial resection. Tumor size (P < .001), grade (P < .001), and microscopic resection margin (P < .001) independently predicted DSS for all STS. Size and grade independently predicted early (DFI CONCLUSION: Tumor size, grade, and resection margin predict outcome for completely resected STS, and their influence for DSS is time- and site-dependent. The influence of prognostic factors changes over the natural history of extremity/trunk STS. Time to recurrence exerts significant influence over complete resection rates for recurrent disease.
SOFT TISSUE SARCOMAS (STS) are rare neoplasms of mesenchymal origin with approximately 8,000 new cases per year in the United States and a mortality rate of 50%.1 Independent prognostic factors for resectable STS are tumor size, depth, histologic grade, completeness of resection, and local recurrence (LR).2-5 Previous studies have identified histologic grade as the most significant independent adverse predictor of early outcome with localized extremity STS; however, prognostic impact of grade diminishes with time.2,6 Preliminary data suggest that resection margin seems to be the only significant variable that influences late (> 5 years) outcome of patients with extremity and retroperitoneal STS.7,8 Disease-free interval (DFI) between primary tumor treatment and tumor recurrence is a significant predictor of outcome in various malignancies.9-12 Although previous analyses have identified LR as a marker for increased risk of distant disease failure and mortality, there is a paucity of studies analyzing impact of time to LR on survival after resection of primary extremity sarcoma.2,13,14 Four retrospective series had no information about the impact of DFI on postrelapse survival.15-18 A number of investigators have found that patients that undergo complete resection of distantly recurrent sarcoma to the lungs after a long DFI (> 1 year) have significantly improved postmetastasis survival over similar patients with early disease relapse.19-24 Prognostic factors for outcomes are defined at the time of initial treatment. Once a patient has survived a defined interval, the prognosis improves as age-adjusted life expectancy increases with each decade of age, and the risk factors for disease relapse and survival change.25 The likelihood of cure as a function of DFI after sarcoma recurrence is incompletely understood. The purpose of this study is to explore the influence of DFI and to define prognostic factors for postrelapse survival and to determine the time-dependent influence of these prognostic variables in a large cohort of patients with completely resected primary STS.
The Memorial Sloan-Kettering Cancer Center Sarcoma Database was created in 1982 and has prospectively maintained clinical, pathologic, treatment, and outcome data on all adult (  16 years) patients with primary and recurrent STS that received treatment at our institution. In the latter years of the study, 212 (10%) patients underwent their surgical procedures as a same-day admission. These patients were no different from those treated in earlier years as inpatients. We reviewed the clinical and pathologic records and updated the follow-up of 2,123 adult patients with localized primary STS (all anatomic sites) that underwent complete resection and were observed at Memorial Sloan-Kettering Cancer Center during the time period of July 1982 to October 1999. Patient follow-up was complete up to July 2001. Follow-up exceeded 2 years for 1,153 of 1,441 (80%) patients alive at the time of last visit. Less than 5% (n = 97) of patients were lost to follow-up. The follow-up schedule varied according to primary tumor site and stage and, although guidelines were available, was not vigorously invoked. Anatomic sites were classified as extremity and superficial trunk (ext/trunk), retroperitoneum (RP), head and neck (H&N), visceral (Visc; gastrointestinal, genitourinary, and gynecologic), and intrathoracic (Thor). Because ext/trunk sarcomas had significantly different disease-specific survival (DSS) than RP, H&N, Thor, and Visc primary tumors by multivariate analysis, the outcome appraisal was conducted in this study according to the two anatomic site categories ext/trunk and RP/H&N/Thor/Visc. Members of the Department of Pathology verified the histologic diagnosis of the primary and recurrent sarcoma with the majority reviewed by three pathologists over the 17-year study period. As critical histopathologic review was conducted on a weekly basis, recorded prospectively, and entered primarily into the database, pathology slides were not re-reviewed for the purpose of this study. Histologic subtype was not included in the analysis of study end points. Potential redefinition of some cases of malignant fibrous histiocytoma was not made. Molecular diagnosis by genetic characterization was performed in recent years. We elected to select those prognostic factors (tumor size, depth, and histologic grade) that comprise the most useful modern staging systems for STS as well as those factors that significantly influence postrelapse survival (anatomic site and microscopic margin) and the intensity of clinical surveillance at our institution (anatomic site and primary tumor stage) after primary tumor resection.18,26 Previous studies have indicated that tumor histology does not predict postmetastasis survival among extremity sarcomas or tumor-related mortality for completely resected retroperitoneal sarcoma.2,4
Tumor size was measured as the maximum diameter of the resected tumor specimen. Tumors were classified into three size categories: All patients in this study had complete resection of their primary STS, defined as the absence of gross residual disease after surgical excision of the tumor. Microscopic margins were defined at the time of histopathologic assessment and categorized as positive (tumor at the inked margin) or negative (no tumor at the inked margin). Adjuvant treatment in the form of radiotherapy or chemotherapy was administered as part of the standard of care or as part of clinical trials. As adjuvant therapy was not prospectively randomized and not uniformly applied, these treatment-related factors are reported, but have been excluded, from the statistical analysis of outcome. Primary end points included time from first operation to first relapse (local, distant, or synchronous) and disease-specific mortality. LR was defined as the first clinical, radiologic, or pathologic evidence of tumor of the same histologic type, within or contiguous to the previously treated tumor bed, after primary tumor therapy. Distant metastasis was defined by clinical or radiologic evidence of systemic disease spread outside the primary tumor basin. Regional nodal recurrences were defined as distant metastasis.
Statistics For LR, only the first LR was considered, and all other LRs were censored. Synchronous LR and DR were considered separately as an event for both LR and DR. In defining disease-related mortality, only deaths that were confirmed to be related to disease were considered in disease-related mortality calculations; all other cases were censored at date of last follow-up. Because desmoid tumor has a low potential for developing DR, all cases with this subtype in the ext/trunk were excluded in analyses involving DR and disease-related mortality. The rates of development of the clinical end points were estimated using the Kaplan and Meier product-limit method. Less than 5% of the study population was lost to follow-up; these patients were censored in survival analysis. The effect of each prognostic factor on the event rate was examined using the log-rank test. Independent prognostic values of the factors were studied using Cox proportional hazards regression. Statistical analyses were performed using JMP and SAS 6.12 (JMP and SAS, Cary, NC) and SPSS 9.0 (SPSS, Chicago, IL). A P value less than .05 was considered significant.
The following factors were studied: patient age ( In the analysis of outcome, disease relapse was categorized in accordance with four recurrence time frames, less than 6 months, 6 to 24 months, more than 24 to 36 months, and more than 36 months. The cutoff points for landmark disease-free time frames were selected arbitrarily before statistical analysis. Time to disease relapse was calculated from the time of primary tumor resection to first LR, DR, or synchronous recurrence. Comprehensive analysis of the time-dependent effect of all factors for each event rate was examined using a time-dependent covariate approach.6,27,28 Times in 6-month intervals up to 5 years were studied to define changes in the prognostic value of factors for the development of LR, distant metastasis, and tumor-related death. Because the same factors are known to confer prognosis differently depending on the site of the tumor when studying the influence of factors on clinical end points, the interaction between factors and site were examined. Cumulative hazard plots were used to confirm time-dependent changes of significant covariates, identified by nonparametric estimates, according to changes in slope of the cumulative hazard curves. Stepwise Cox models were fit to the data for the clinical end point of DSS separately for the entire cohort and each of the two site categories (ext/trunk v RP/H&N/Thor/Visc) within each time frame. A three-step approach was used for time-dependent data analysis. In the first step, a stepwise Cox model was developed for each clinical end point based on all study patients. This step identified the independent prognostic value of tumor site. In the second step, stepwise Cox models were fit to the data for each clinical end point separately for each of the two site categories (ext/trunk v RP/H&N/Thor/Visc). Factors that were found to be prognostic were all examined for changes in their influence over time. In the final step, a single Cox model was fit to all the data, incorporating interactions and change points.
The results will be presented in two major sections: (1) impact of DFI on DSS and (2) time-dependent analysis. The degree to which DFIs of 2 and 5 years influence DSS are presented according to tumor site category (ext/trunk and RP/H&N/Thor/Visc) as well as tumor grade and size (low grade,
Summary Outcome Data The clinical, pathologic, and treatment characteristics of the study population are listed in Table 1 and recurrence and survival data in Table 2. Median follow-up for patients alive at the time of last follow-up was 58.9 months (interquartile range, 27.3 to 110.1 months). Of the 2,123 patients treated for localized primary sarcoma, 37% (n = 788) developed recurrence during follow-up. DFI after complete primary tumor resection ranged from 4 months to 16 years. At the time of last follow-up, 63% (1,342 of 2,123) of patients were alive disease-free, and 23% (493 of 2,123) had died of disease.
DSS: Impact of DFIs of 2 and 5 Years Two-, 5-, and 10-year DSS for completely resected primary sarcomas (all anatomic sites) were 88%, 76%, and 67%, respectively (Fig 1A). For patients that remained disease-free 2 years after resection, the survival rates for the next 2, 5, and 10 years (4, 7, and 12 years after resection) were 97%, 90%, and 82%, respectively. DSS after a DFI of 5 years at 2, 5, and 10 years (7, 10, and 15 years after primary tumor resection) were 99%, 96%, and 92%, respectively.
Overall 2-, 5-, and 10-year DSS for patients with completely resected primary ext/trunk sarcomas were 89%, 79%, and 71% and 86%, 69%, and 56%, respectively, for RP/H&N/Thor/Visc sarcomas. Corresponding DSS rates according to 2-year and 5-year DFIs are demonstrated in Figs 1B and 1C. The trend of improved survival with increasing time to recurrence was evident for both anatomic site categories. Figure 2A depicts the DSS by tumor grade and size for primary sarcomas (all sites) and demonstrates the dominant influence of histologic grade on outcome. Survival was well stratified by size category among low- and high-grade sarcomas.
The distribution of survival by grade and size was preserved across site categories, but the prognosis differed by site (Fig 2B and 2C). Primary tumor site seemed to have little influence over the uniformly favorable early (2-year DSS) outcome among low-grade tumors. However, late outcome ( 5 years) was significantly worse for large, low-grade RP/H&N/Thor/Visc than ext/trunk sarcomas. The overall early DSS among the two site categories for high-grade tumors was more favorable for ext/trunk than RP/H&N/Thor/Visc sarcomas. The difference in outcome for high-grade sarcomas according to site became more pronounced with time. Two-, 5-, and 10-year DSS rates overall and for more than 2- and 5-year DFIs for ext/trunk and RP/H&N/Thor/Visc sarcomas according to primary tumor grade and size are listed in Table 3. After a DFI of more than 2 years, there was an incremental increase in survival across all size, grade, and site categories. For patients surviving more than 5 years free of disease with either ext/trunk or RP/H&N/Thor/Visc sarcoma, the survival over the ensuing 5 years (10 years from primary tumor resection) was not significantly different across tumor grade and size categories.
Site and Time to Recurrence: Influence on Subsequent Survival Two thirds of patients that recurred did so within 2 years of primary tumor resection. Fifteen percent of all recurrences developed during the third year of clinical surveillance. Eighteen percent of patients relapsed after a DFI of 3 years and 9% of patients after a DFI exceeding 5 years. Likelihood of complete resection of recurrent sarcoma increased with DFI. Nine percent of patients with DFI less than 6 months were alive disease-free at last follow-up (median survival, 115 months), whereas 33% of those with DFI more than 3 years (median survival, 98 months) could be rendered disease-free after re-resection (Table 4). Forty percent of patients that recurred 5 or more years after primary tumor resection were alive and free of disease at last follow-up (median survival, 115 months). Five-year postrecurrence DSS for early (DFI < 6 months) and late (DFI > 36 months) recurrence groups were 19% and 69%, respectively. This is likely attributable to higher incidence of distant metastases in the early disease failure subset.
Sixty-nine percent of patients with less than 6 months DFI had more than 5 cm of high-grade, deep primary sarcomas, of which only two (1.8%) could be rendered disease-free after recurrence. Forty percent of patients that recurred after a DFI exceeding 3 years had more than 5 cm of high-grade, deep primary tumors. A third of these patients were alive disease-free at time of last follow-up. The factors that significantly influenced postrecurrence survival differed according to DFI. Multivariate analysis of tumor-related mortality as a function of DFI demonstrated that histologic grade was the most significant outcome predictor within the first 3 years after resection of the primary STS. The prognostic significance of histologic grade for postrecurrence survival decreased as a function of DFI. The importance of microscopic resection margins became evident later (> 36 months) in the natural history of the disease (Table 4). Although the likelihood of complete resection of recurrent RP/H&N/Thor/Visc STS increased with time to first recurrence, these rates were lower overall when compared with ext/trunk tumors (DFI > 36 months; 26% v 37%). Median postrelapse survival was 2.3 times longer (46 v 20 months) for isolated LR in the ext/trunk than RP/H&N/Thor/Visc. The effect of systemic disease was uniformly poor across all tumor sites because survival after distant disease failure did not differ according to tumor site, although it did progressively increase with DFI.
Impact of Changes in Influence of Prognostic Variables Over Time on Site-Specific Outcome
Time-Dependent Analysis: Rate of Developing LR
Time-Dependent Analysis: Rate of Developing DR For patients with primary ext/trunk STS, independent factors predictive of DR were a high grade (P < .001), a size more than 5 cm (P < .001), a size more than 10 cm (P < .001), deep location (P = .01), and positive microscopic margins (P = .03). The influence of grade and size changed over time for ext/trunk STS. The RR of high grade for distant metastasis was 8 in the initial 36 months after surgery, but that changed to 2 afterward (P < .001). Similarly, compared with patients with primary tumors  5 cm, those with tumors more than 5 cm had a RR of 3 in the first 12 months, but this RR reduced to 1.5 afterward. The independent adverse prognostic factors for DR among RP/H&N/Thor/Visc sarcomas were a high grade (P < .001) and a size more than 5 cm (P < .001). The results of the analysis for the entire study cohort are summarized in Table 5. Compared with patients with low-grade tumors, those with high-grade ext/trunk tumors could expect their risk of developing distant metastases to reduce from 7.44 to 2.75 (7.44 x 0.37) if they survived free of DR 36 months after primary tumor resection. However, for patients with high-grade tumors arising in other sites, their RR remained at 7 throughout their lifetime (Fig 4).
Time-Dependent Analysis: Rate of Disease-Specific Mortality Independent predictors of tumor-related mortality for ext/trunk sarcomas were a high grade (P < .001), a size more than 5 cm (P < .001), a size more than 10 cm (P < .001), deep location (P = .05), and positive microscopic margin (P = .02). The influence of grade (P = .03) and size (P = .02) changed over time. The RR of tumor-related mortality for high-grade ext/trunk sarcomas changed from 7.6 in the initial 42 months after surgery to approximately 3.0 afterward. Similarly, compared with patients with tumors 5 cm, those with tumors more than 5 cm in size had a RR of 3.3 in the first 24 months. This risk of tumor-related mortality was reduced to 1.6 thereafter. Although microscopic resection margin did not seem to influence early outcome, the RR of tumor-related death for positive resection margins increased (RR, 1.3) 36 months after primary tumor resection. Prognostic factors for tumor-related mortality for RP/H&N/Thor/Visc sarcomas were a high grade (P < .001), a size more than 5 cm (P < .001), and positive margins (P < .01). The results of the analysis of tumor-related mortality for the entire study population are listed in Table 5. Patients with ext/trunk sarcoma could expect their risk of dying of disease to be significantly reduced if they survived 3 years after resection. However, for patients with tumors arising in the RP/H&N/Thor/Visc, the influences of high-risk factors remained throughout the patient’s lifetime.
The observation that the DFI between resection of the primary cancer and subsequent tumor recurrence significantly impacted survival has been made by investigators evaluating various malignancies including malignant melanoma, breast, and renal carcinoma.9-12,29 A short recurrence-free interval correlates with a biologically aggressive pattern of disease; this principle applies, along with site and number of metastases, to the surgical management of metastatic STS. Although the primary cause of tumor-related death for patients with ext/trunk STS is related to widespread metastatic disease, several series have demonstrated that long-term survival is possible after pulmonary metastasectomy in highly selected patients.20-24,30,31 In these studies, a significant correlation has been consistently demonstrated between DFI exceeding 1 year and postresection survival in patients with STS. In addition to age, comorbid disease, and pattern of metastatic disease, DFI is an important consideration in the selection of patients with sarcoma for metastasectomy. The prognostic implications of isolated LR early after potentially curative resection of primary STS remain incompletely understood.15-18 Median postrecurrence survival was significantly improved in patients with recurrence-free intervals exceeding 12 months for locally recurrent ext/trunk (50.4 v 29.8 months; P < .01) and retroperitoneal (49.9 v 9.9 months; P = .03) STS. DFI was also predictive of rendering a patient free of disease after any recurrence, irrespective of anatomic site of origin. For all primary STS in this study, the likelihood of rendering a patient disease-free who had recurred within 6 months of resection of a large (> 5 cm), high-grade, deep tumor was 2%. In identically staged patients that recurred after a 3-year DFI, 30% were rendered free of disease with re-resection. The prognostic factors that were independently associated with freedom from LR and DR were site dependent. Tumor grade, size, and microscopic resection margin were independent predictors of DSS for all completely resected primary STS. Depth was not significant. One reason for this could be the high association of deep location with positive margins, such that when margin status was entered into the Cox model, depth was no longer significant. Primary tumor location seems to be an important determinant of outcome after sarcoma recurrence, as a recent study identified primary tumor anatomic site as an independent predictor of DSS among locally recurrent STS in the absence of synchronous distant metastasis that could be resected completely.18 In the larger, current study, anatomic site exerted a significant influence over postrelapse survival. Patients with STS arising in either ext/trunk or RP/H&N/Thor/Visc sites had progressively improved survival with increasing freedom from recurrence interval. Although, the likelihood of complete resection of primary tumor site disease failure increased with time to recurrence for both site categories, the complete resection rates were lower overall for RP/H&N/Thor/Visc than ext/trunk tumors. The effect of systemic disease was uniformly poor across all tumor sites because survival after distant disease failure did not differ according to tumor location, although it did increase with DFI. Compared with patients with primary tumor ext/trunk STS, those with RP/H&N/Thor/Visc tumors more than 5 cm had a two-fold increased risk of developing local failure at the primary tumor site beyond 24 months after primary tumor resection. The effect of ext/trunk tumor size and grade for DR-free survival was most pronounced in the early course of the disease and progressively diminished over time. The independent adverse prognostic influence of grade for distant metastasis remained constant throughout the lifetime of the patient with RP/H&N/Thor/Visc sarcoma. The influence of high-risk factors for tumor-related mortality was decreased significantly over time for ext/trunk sarcomas; the RR of sarcoma-related death remained constant for the lifetime of the patient with primary RP/H&N/Thor/Visc STS. Our findings demonstrate that the frequency of sarcoma recurrence and the factors predictive of disease relapse vary according to length of follow-up. Tumor-related factors (size and grade) reflective of tumor biology are predictive of mortality in the setting of early recurrence, and the treatment-related factor of microscopic margin status becomes predictive of survival only when recurrence occurs after 36 months of follow-up. Previous publications from our institution have not found histologic grade to be predictive of LR for localized extremity STS.2,6 The present analysis for the ext/trunk group in this study included tumors originating in the chest and abdominal wall, breast, and buttock, an unfavorable prognostic subset of patients (largely composed of large, deep, and high-grade tumors) that were more likely than patients with extremity or breast sarcoma to have microscopic margin positive resection. In a previous study of 2,084 patients with completely resected STS, positive microscopic resection margin was found to be an independent predictor of local failure in patients with ext/trunk sarcoma.3 The median follow-up in the study of Pisters et al2 was 47 months compared with 59 months in the current study. Nearly 25% of LRs in the present study developed after a DFI exceeding 36 months. Previous reports have underscored the importance of follow-up duration in the interpretation of survival data.24 The fact that this study was not population-based suggests that referral bias may influence the result in that we may have identified a high-risk subset of patients. It is possible that referral patterns have changed, but a recent study from this institution found little influence of referral over outcome-based analysis.32 The majority of same-day resections of sarcoma were performed in the last 4 years of the study. Such patients had biologically favorable, early-stage tumors; however, this subset represents 13% of the entire study population. This report confirms the previously published data indicating that the majority of recurrences develop within 2 years of resection of primary STS.2,22,33,34 The findings that 9% of recurrences developed after a DFI exceeding 5 years and that first recurrences were detected as late as 16 years after definitive resection underscore the need for long-term surveillance. Formalized clinical follow-up programs have been developed based on the premise that early detection and treatment of recurrent sarcoma improves survival; however, there is a paucity of data to support this hypothesis.35,36 The majority of follow-up algorithms are based on retrospective data and consensus rather than objective evidence of survival benefit. A survey of the members of the Society of Surgical Oncology demonstrated that despite wide variation in follow-up practices, the frequency of office visits and radiographic surveillance increased with tumor size and grade and decreased with postoperative year.37 Our current follow-up frequency and intensity is based on disease stage. The surveillance algorithm reflects the biology of these tumors such that surveillance cross-sectional imaging is applied selectively to limit excessive radiologic surveillance to situations where new findings would alter management. Analysis of the changes of influence over time of established prognostic factors demonstrated that tumor biology governs early tumor-related mortality, whereas microscopic resection margins influence late outcome. Early recurrence was found to be predictive of an inability to cure the patient of disease. This study reinforces the need to consider the timing and pattern of recurrence in the selection of patients for surgical treatment of recurrence and represents an initial step in the appraisal of the time-dependence of prognostic variables in sarcoma. Although it does not specifically address all variables that may potentially influence postrelapse survival, there are sufficient data to allow generalizations to be made by physicians providing follow-up care to patients with STS, including how the patient should be advised once a recurrence is detected and what the likelihood is of rendering that patient disease-free once the tumor has recurred.
Supported in part by grant no. P01-CA47179 (to M.F.B.) from the National Institutes of Health, Bethesda, MD. We acknowledge the important contributions of S. Hajdu, MD, J. Woodruff, MD, and C. Antonescu, MD, to histopathologic analysis of tumors included in this report.
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19. Vezeridis MP, Moore R, Karakousis CP: Metastatic patterns in soft-tissue sarcoma. Arch Surg 118: 915-918, 1983 20. Putnam JB Jr, Roth JA, Wesley MN, et al: Analysis of prognostic factors in patients undergoing resection of pulmonary metastases from soft tissue sarcomas. J Thorac Cardiovasc Surg 87: 260-268, 1984[Abstract] 21. Jablons D, Steinberg SM, Roth J, et al: Metastasectomy for soft tissue sarcoma: Further evidence for efficacy and prognostic indicators. J Thorac Cardiovasc Surg 97: 695-705, 1989[Abstract] 22. Casson AG, Putnam JB, Natarajan G, et al: Five-year survival after pulmonary metastasectomy for adult soft tissue sarcoma. Cancer 69: 662-668, 1992[CrossRef][Medline] 23. Gadd MA, Casper ES, Woodruff JM, et al: Development and treatment of pulmonary metastases in adult patients with extremity soft tissue sarcoma. Ann Surg 218: 705-712, 1993[Medline] 24. Billingsley KG, Burt ME, Jara E, et al: Pulmonary metastases from soft tissue sarcoma. Ann Surg 229: 602-612, 1999[CrossRef][Medline] 25. Birth, marriages, divorces and deaths: Provisional data for October 2001. Natl Vital Stat Rep 50:1-2, 2002 26. Wunder JS, Healey JH, Davis A, et al: A comparison of staging systems for localized extremity soft tissue sarcoma. Cancer 88: 2721-2730, 2000[CrossRef][Medline] 27. Cox DR: Regression models and life tables. J R Stat Soc B 34: 187-220, 1972 28. Kalbfleisch JD , Prentice RL: The Statistical Analysis of Failure Time Data. New York NY, Wiley & Sons, 1980, pp 119-142 29. Kavolius JP, Mastorakos DP, Pavlovich C, et al: Resection of metastatic renal cell carcinoma. J Clin Oncol 16: 2261-2266, 1998[Abstract] 30. van Geel AN, Pastorino U, Jauch KW, et al: Surgical treatment of lung metastases: The EORTC Soft Tissue and Bone Sarcoma Group study of 255 patients. Cancer 77: 675-682, 1996[CrossRef][Medline] 31. Roth JA, Putnam JB, Wesley MN, et al: Differing determinants of prognosis following resection of pulmonary metastases from osteogenic and soft tissue sarcoma. Cancer 55: 1361-1366, 1985[CrossRef][Medline] 32. Lewis JJ, Leung D, Espat J, et al: Effect of reresection in extremity soft tissue sarcoma. Ann Surg 231: 655-663, 2000[CrossRef][Medline] 33. Whooley BP, Gibbs JF, Mooney MM, et al: Primary extremity sarcoma: What is the appropriate follow-up? Ann Surg Oncol 7: 9-14, 2000[Abstract] 34. Sauter ER, Hoffman JP, Eisenberg BL: Part I: Diagnosis and surgical management of locally recurrent soft tissue sarcoma of the extremity. Semin Oncol 20: 451-455, 1993[Medline] 35. Demetri GD: NCCN: Sarcoma. Cancer Control 8: 94-101, 2001 (suppl 6)[Medline] 36. Brennan MF: Follow-up is valuable and effective: True, true and unrelated? Ann Surg Oncol 7: 2-3, 2000[CrossRef][Medline] 37. Beitler AL, Virgo ES, Johnson FE, et al: Current follow-up strategies after potentially curative resection of extremity sarcomas. Cancer 88: 777-785, 2000[CrossRef][Medline] Submitted July 27, 2001; accepted July 11, 2002.
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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. Outcome was classified according to sites of first disease recurrence. The clinical outcomes studied were time to first LR, time to first distant recurrence (DR), and time to tumor-related mortality. 
