From the Departments of Surgery (Drs Lewis and Brennan), Biostatistics (Dr Leung), Medicine (Dr Casper), and Pathology (Drs Woodruff and Hajdu), Memorial Sloan-Kettering Cancer Center, New York, NY. Dr Hajdu is now with the Department of Pathology, North Shore University Hospital, Manhasset, NY.

ABSTRACT

BackgroundThe majority of survival studies in patients with extremity soft tissue sarcoma have focused on early recurrence and mortality. There are few data addressing long-term follow-up and survival.

ObjectiveTo analyze survival and recurrence in patients with extremity soft tissue sarcoma who survive for more than 5 years.

MethodsPatients who underwent treatment for primary tumors (July 1982 to July 1994) and were followed up for more than 5 years were the subject of study. Disease-specific and disease-free survival were determined actuarially. Significance was evaluated using log-rank testing for univariate analysis and Cox model stepwise regression for multivariate analysis.

ResultsA total of 495 patients with primary extremity tumors were treated before July 1989 and eligible for 5-year follow-up. Of these, 282 have been followed up for more than 5 years (median follow-up, 84.4 months). Actuarial disease-specific survival of patients who survive for longer than 5 years was 79%±7% (±SEM) at 10 years, and of those who were metastasis free at 5 years was 91%±4% at 10 years. On univariate analysis, post–5-year disease-specific survival was influenced by positive microscopic margin and initial tumor size of 5 cm or greater. On multivariate analysis, post–5-year disease-specific survival was influenced only by positive margins.

ConclusionsBased on these analyses, 21% of patients with primary extremity sarcoma who survive for 5 years will die of disease within 5 years. Even of those who are metastasis free at 5 years, 9% will die of disease within 5 years. In contrast to early mortality, tumor grade has no influence on post–5-year prognosis. Patients with positive microscopic margins are at risk for post–5-year disease-specific mortality and therefore require long-term follow-up and consideration for investigational therapy.

Figures in this Article

SOFT TISSUE sarcomas are rare and unusual neoplasms, with an annual incidence in the United States of approximately 5000 to 6000 persons. Although these tumors may develop in any anatomic site, approximately 50% will occur in the extremities. Current staging systems for extremity sarcomas, based on short-term outcome, focus on histological grade of the tumor, the size of the primary tumor, and the presence or absence of metastasis.1,2 Histological grade is a major prognostic determinant and is based on differentiation, cellularity, mitotic activity, presence of necrosis, stromal content, and vascularity. Low-grade lesions are assumed to have a low (<15%) risk of subsequent metastasis and the high-grade lesions a high (>50%) risk of subsequent metastasis. Although size has historically been considered a less important determinant of biologic behavior, this bias is predicated on measurement of early recurrence and mortality events. It would appear that grade is a factor in early metastasis and size is a feature of more delayed metastasis.2

The majority of survival and biology studies in patients with extremity soft tissue sarcoma focus on early recurrence and mortality, and there are few data addressing long-term follow-up and survival.3 Furthermore, the relatively small number of cases and their diversity in anatomic location, histological appearance, and biologic behavior make the comparative analysis of survival difficult. The objective of this study was to analyze disease-specific and disease-free survival in patients, treated and followed up at a single institution, who survive for more than 5 years. In addition, we compared these long-term survivors with patients who died of their disease within 5 years.

PATIENTS AND METHODS

PATIENTS

A prospective database of all adult patients (>16 years) with soft tissue sarcoma, treated at Memorial Sloan-Kettering Cancer Center, New York, NY, was established in July 1982. This database is defined by the accrual and entry of clinical, pathologic, and treatment data of all consecutive patients at the time of initial presentation, with patients then prospectively followed up for recurrence and survival. Patients who underwent treatment for primary extremity soft tissue sarcoma before July 1989 and were therefore eligible for longer than 5-year follow-up (through July 1994) or those who died of disease within 5 years were the subject of this study. Clinical and pathologic variables were correlated with survival end points. Patient variables analyzed included age at diagnosis (<60 or ≥60 years), sex, and race. Tumor variables included size (<5 or ≥5 cm), histological grade (low or high), depth (superficial or deep), microscopic margins (negative or positive), and histological subtype. The histopathologic subclassification has been monitored by 2 pathologists (J.W. and S.I.H.) during this time. Histological grade was divided into low or high, distinct from other aspects of intermediate transition.2,4 Depth was defined by the relationship of the tumor to the deep fascia. Because treatment was not prospectively randomized, but included both patients prospectively randomized in trials5,6 and those given standard of care based on prognosis,3 the inclusion of treatment variables in any of the analyses would confound the effects of other factors. Therefore, while we report the treatment data, we have chosen not to include them in any of the analyses.

STATISTICS

Pre– and post–5-year disease-specific and disease-free survivals were modeled with the Kaplan-Meier method.7 Deaths that were confirmed to be caused by the disease were treated as an end point for disease-specific survival; other deaths were treated as censored observations. Disease-free survival was segregated into local recurrence-free and metastasis-free survival. Survival curves were compared using log-rank testing for univariate analysis and Cox model stepwise regression for multivariate influence. To arrive at a parsimonious multivariate model, covariates were selected only if they contributed significantly to the fit of the model. The influence of time of metastasis on survival was analyzed using the approach of dynamic cohorts. Comparison between patient and tumor categorical variables in different groups was performed using the Fisher exact test for univariate analysis and logistic regression for multivariate analysis.

RESULTS

PATIENTS

During the period under study we treated 818 patients with extremity soft tissue sarcoma. This included 495 patients who presented with primary tumor and 323 patients who presented with recurrent tumor (initially treated either at a referring institution or at Memorial Sloan-Kettering Cancer Center before July 1982). The 495 patients with primary tumor constituted the study group. At 5 years' follow-up, 111 patients died of disease (early mortality), and 14 died with no evidence of disease. Eighty-eight patients were alive at last follow-up but did not complete 5-year follow-up. This included patients from out of state or from foreign countries who were lost to long-term follow-up. The median follow-up of this group was 3.4 years and they were excluded from analysis. There were 282 patients with greater than 5-year follow-up and this group constituted the long-term survivors. There were no significant differences in age or sex between the long-term survivor group and the early mortality group (Table 1). Distribution of primary surgical and adjuvant radiation treatment in long-term survivors is shown in Table 2, top.

Table Graphic Jump LocationTable 1.Clinical and Pathologic Characteristics From Patients Alive at 5 Years vs Those Dead of Disease Within 5 Years

TUMOR CHARACTERISTICS

Comparison of tumor characteristics between patients with early mortality (died of disease at <5 years) and long-term survivors (alive at >5 years) is summarized in Table 1. Not surprisingly, histological high grade, large size (≥5 cm), deep lesion, and positive microscopic margins, and not the histological subtype, were significant predictors on univariate analysis of early mortality. Logistic regression analysis of risk of death within 5 years, vs survival or death after 5 years, revealed histological high grade as the dominant risk factor (P<.001; odds ratio, 7.7).

DISEASE-SPECIFIC SURVIVAL

Of patients alive at 5 years, within a median follow-up time of 84.4 months, 23 patients died of disease. Actuarial survival for the group of 282 patients alive at 5 years was 79%±7% (±SEM) at 10 years. There was no difference in survival when patients with histological high-grade tumors were compared with those with low-grade tumors (P=.80). In contrast, both large size and positive microscopic margins adversely influenced survival. Patients with large (≥5 cm) tumors did worse compared with those with small (<5 cm) tumors (P=.03). Similarly, those with positive microscopic margins did worse compared with those with negative margins (P=.01; Figure 1). Results of a Cox model multivariate analysis, for disease-specific survival, are summarized in Table 3. Positive microscopic margin (P=.02; risk ratio, 2.7) was the dominant factor influencing long-term survival. Distribution of primary surgical and adjuvant radiation treatment in patients with positive microscopic margins is shown in Table 2, bottom.

DISEASE-FREE SURVIVAL

Disease-free survival was segregated into local recurrence-free and metastasis-free survival. Among the 282 long-term survivor patients, 23 had local recurrence without distant metastases, 20 developed distant metastases without local recurrence, and 13 developed both local and distant disease. Local recurrence was predicted in patients with positive microscopic margins (P=.01 on both univariate and multivariate analyses; risk ratio, 2.1) and patients older than 60 years at time of diagnosis (P=.03 on multivariate analysis; risk ratio, 2.1). When other factors had been corrected for, development of local recurrence did not influence metastasis-free or disease-specific survival.

Of the 282 long-term survivors, 20 developed metastases within 5 years and 13 developed metastases after 5 years; actuarial 10-year metastasis-free survival was 75%±5%. Of the 262 patients alive and metastasis free at 5 years, 9 went on to die of sarcoma metastases after 5 years. The 10-year actuarial disease-specific survival of patients who were disease free at 5 years was 91%±4%. When measured as a function of time of metastasis, there was no difference in disease-specific mortality (P=.13) between those who had metastases before 5 years or those who had metastases after 5 years. There was no difference between small (<5 cm) and large (≥5 cm) tumors on metastasis-free survival (P=.07). This was in contrast to the significant influence of microscopic margins (Figure 2) on metastasis-free survival (P=.009). In a multivariate Cox model (Table 3), both deep tumor (P=.03; risk ratio, 2.6) and positive microscopic margin (P=.02; risk ratio, 4.6) influenced metastasis-free survival.

Place holder to copy figure label and caption

Figure 2

Metastasis-free survival for patients with extremity soft tissue sarcoma alive at 5 years, segregated by microscopic margins at primary resection. Positive microscopic margin was a significant predictor for development of metastasis.

COMMENT

The majority of survival and biology studies in patients with soft tissue sarcoma has focused on early recurrence and mortality, and there are few data addressing long-term follow-up and survival. This study analyzes disease-specific and disease-free survival in patients with primary extremity soft tissue sarcoma, treated at a single institution, who survived for more than 5 years. In addition, we have compared these long-term survivors with those who died of disease prior to 5 years. There are 3 novel and significant findings in this study. First, 21% of patients who are alive at 5 years will die of disease during the next 5 years; of those metastasis free at 5 years, 9% will die of disease during the next 5 years. Second, tumor histological grade, which is the pivotal variable influencing early outcome, has no influence on the subsequent survival of patients who are alive at 5 years. Third, positive microscopic margins, at the time of initial surgical resection, adversely impact the disease-specific survival of patients who are alive at 5 years.

From July 1982 to July 1989, we treated 818 patients with extremity soft tissue sarcoma. All patients were then prospectively followed up. Within this group, 495 patients were treated for primary tumor and of these 282 were alive at 5 years. The median follow-up time of the 282 patients was 84.4 months. After 5 years, 23 patients died of documented disease and the actuarial survival at 10 years was 79%. All disease-related deaths occurred in patients who had metastatic disease. Univariate analysis identified 2 prognostic variables for disease-specific mortality: tumor size of 5 cm or greater and microscopic margin of the resected specimen positive for tumor. Notable was the finding that histological high grade was not identified as a prognostic factor for disease-specific mortality after 5 years. Multivariate analysis revealed positive microscopic margin to be the dominant variable influencing post–5-year disease-specific survival. Positive microscopic margin and age older than 60 years at time of initial diagnosis predicted development of local recurrence. Development of local recurrence did not influence metastasis-free or overall survival. Positive microscopic margin did, however, predict the development of subsequent metastasis, both prior to and after 5 years.

The correlation between positive microscopic margin and local recurrence in extremity soft tissue sarcoma is well documented.8- 10 While some studies have reported a correlation between positive microscopic margins and metastasis and disease-specific mortality, the specific role of margins remains controversial.9,11 Although it is apparent that positive margins are reflective of more aggressive tumor biologic behavior,12- 14 it is possible that residual microscopic disease may also represent a nidus for tumor dissemination.15 The findings in our study suggest that microscopic margins are important predictors of metastasis, and disease-specific death, when patients are followed up long-term. Whether this is due to a biologic correlative epiphenomenon or residual nidus for subsequent tumor dissemination is speculative. The influence of local control on the margins, on disease biology, and on disease-specific survival for patients with extremity soft tissue sarcoma is unclear and controversial.16,17

Two prospective randomized trials have evaluated local control and survival in the context of defining treatment. In a randomized trial from the National Cancer Institute8 comparing amputation vs conservative surgery plus radiation, local recurrence rates were 19% in the limb-sparing arm vs 6% in the amputation arm. Despite this observation, overall survival rates were equal at 70% (limb-sparing) vs 71% (amputation). In a randomized prospective trial from Memorial Sloan-Kettering Cancer Center5,6 evaluating the role of brachytherapy in 126 patients with extremity sarcoma, adjuvant brachytherapy was found to substantially improve local control in patients with high-grade sarcomas. This improvement in local control, however, did not translate into any improvement in overall survival. Our present findings support those of these studies. Despite our observation that positive microscopic margin predicted the development of subsequent metastasis and mortality, development of local recurrence did not influence metastasis-free or overall survival. We did not include treatment variables in any of the analyses because treatment was not randomized in all long-term survivors.

The influence of histological tumor grade on early outcome is well established. Indeed, an earlier retrospective review from 13 institutions found the histological grade of the tumor to be the critical determinant of outcome.1 We recently affirmed the remarkable discriminatory effect of grade, and it was our impression that grade is a factor in early metastasis.2 Our present findings confirm these data. Multivariate analysis of risk of death within 5 years, vs survival or death after 5 years, revealed histological high grade as the dominant risk factor for early death. It is therefore not surprising that histological high grade has no influence on late survival. While large tumor size may be important in long-term survival, our sample was too small to get a clear answer. We have also previously observed that patients with tumors smaller than 5 cm have an excellent prognosis.18 These data are supported by the long-term follow-up of these patients. The corollary of these observations is that even when patients do survive to 5 years, 21% will still be expected to die of disease during the next 5 years.

The implications of our findings are 3-fold. First, patients with extremity soft tissue sarcoma require long-term follow-up, and in addition to patients with high-grade or large tumors, those with positive microscopic margins should be considered for investigational adjuvant therapy. Second, interpretation of novel therapeutic interventions for extremity soft tissue sarcoma, while focusing on early outcome, must include long-term follow-up. Finally, prospective clinicopathologic databases, such as the one used in this study, expand our biologic understanding of the natural history of diseases and may benefit patient management considerably.

Metastasis-free survival for patients with extremity soft tissue sarcoma alive at 5 years, segregated by microscopic margins at primary resection. Positive microscopic margin was a significant predictor for development of metastasis.

Correspondence

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