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Status of Surgical Margins and Prognosis in Adult Soft Tissue Sarcomas of the Extremities: A Series of Patients Treated at a Single Institution

From the Department of Surgery, Department of Cancer Medicine, Department of Biostatistics, Department of Pathology, and Department of Diagnostic Imaging and Radiotherapy, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy

Address reprint requests to Alessandro Gronchi, MD, Department of Surgery, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian,1 - 20133 Milano, Italy; e-mail: alessandro.gronchi{at}istitutotumori.mi.it

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
PURPOSE: To explore the prognostic effect of microscopic marginal status after surgery for extremity soft tissue sarcomas.

PATIENTS AND METHODS: We analyzed 911 consecutive patients surgically treated throughout a 20-year span at a single referral center. Six hundred forty-two were first seen with a primary tumor, and 269, with a locally recurrent tumor. All patients underwent macroscopically complete resection. Microscopic marginal status was negative (tumor size > 1 mm) in 748 patients and positive ( 1 mm) in 163 patients. Median follow-up was 107 months.

RESULTS: Patients with primary disease had a lower disease-specific mortality in comparison to those first examined for recurrence (25% v 37%, respectively, at 10 years). Size, malignancy grade, depth, histotype, and local recurrence had a statistically significant prognostic effect at multivariable analysis, while microscopically positive surgical margins had not, though a trend in favor of negative margins was observed. However, an extra risk was observed for patients with positive margins after 3 to 5 years (hazard ratio, 1.8 after 5 years v 0.8 before 5 years). In patients treated for a local recurrence, the prognostic impact of positive margins was higher (hazard ratio, 1.6).

CONCLUSION: Positive surgical margins had a weak adverse prognostic effect, which was more pronounced for those patients escaping an early relapse. This would seem to justify a policy of surgical adequacy in adult soft tissue sarcomas, though clinical decision making in borderline presentations for conservative surgery might be reasonably flexible and shared with the patient. Once a local relapse has occurred, the impact of local treatments seems more critical.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Adult soft tissue sarcomas (STSs) are a group of rare neoplasms of mesenchymal origin, with an expected incidence of 1.5 to 2 cases per 100,000 inhabitants per year, and an overall mortality rate of 30% to 50%.^1,2 Among them, extremity STSs (ESTSs) account for approximately 50% of all STS.¹ While tumor size, histologic grade, depth, and possibly histologic subtype, as well as occurrence of local recurrence, are considered as independent prognostic factors,^3-10 factors related to the quality of treatment are still a matter for debate.^11-17 In particular, the pathologic assessment of the quality of resection margin status is regarded as the benchmark (though imperfect) for determining the quality of local treatment, though the prognostic effect of resection margin status is controversial. Published studies either from retrospective series^11-17 or from randomized trials comparing different local treatment modalities^18-20 have given contradictory results.

A correct understanding of the prognostic effect of the quality of local treatment (that is, the status of resection margins) and local recurrence is essential. If local recurrence is merely a problem of local control that does not affect overall survival, the performance of closer surgical margins with a consequent lower loss of function may be advantageous. However, if local recurrence has by itself a substantial influence on survival, wider surgical margins would be indicated, and larger sequelae accepted.

In this study, we decided to retrospectively assess the impact of surgical margins on disease outcome in a consecutive case series of patients treated at our institution throughout a 20-year time span.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
Between January 1980 and December 2000, 1,013 consecutive adult patients with localized ESTSs were operated on with an eradicating intent at the Istituto Nazionale per lo Studio e la Cura dei Tumori of Milan, Italy.

From this series, we excluded 11 patients who could not undergo a complete surgical excision and 91 patients affected by dermatofibrosarcoma protuberans, as this tumor rarely metastasizes. Thus, our sample includes 911 patients, whose main characteristics are summarized in Table 1 and detailed throughout this section.

A total of 87 major exarticulations (30 major amputation, 30 disarticulation, and 27 forequarter amputations) were performed—50 at presentation at our center (33 in primary cases and 21 in recurrences) and 37 for further recurrences. All surgical resections were considered macroscopically complete, which was defined as being in the absence of gross residual disease after surgical excision of the tumor. Margins were defined at the time of the pathological assessment by a dedicated pathologist. The surgical specimen was always examined in the presence of the operating surgeon. The margins were inked and separately sampled. The closest margin was microscopically categorized as positive (tumor within 1 mm from the inked surface) or negative (absence of tumor within 1 mm from the inked surface). Therefore, resection margins were classified as negative in 748 cases (82%; 556 in primary tumors and 192 in recurrences) and positive in 163 cases (86 in primary tumors and 77 in recurrences).

Radiation therapy was delivered as an adjunct in 340 cases (37%; 37 among primary presentations and 103 among recurrences). The indication to radiation therapy was given by both the operating surgeon and the radiation oncologist when a higher risk of recurrence was supposed to exist on clinical grounds. However, no prospectively selected criteria were used to this end. In particular, radiation therapy was administered to 92 patients (56%) with positive tumor margins as compared with 248 patients (33%) with negative tumor margins. External beam radiation was used in all such cases, and doses ranged from 45 to 65 Gy (median, 57 Gy).

Chemotherapy was given to 179 patients (20%; 114 primary cases and 65 recurrences) at the discretion of the multidisciplinary Soft Tissue Sarcoma Group of our institution or as part of clinical trials. Antracycline-based regimens were used in most of the cases associated with ifosfamide.

As of June 2003, the median follow-up duration of the entire group was 107 months (interquartile range, 58 to 130). Forty-six patients (5%) were lost to follow-up before the 10th year.

The end points of this study were cause-specific mortality, local recurrence, and distant metastasis. Time to occurrence of any event was computed from the date of surgery at our institution to the date when the event was first recorded, or censored at the date of last follow-up assessment in event-free subjects. These end points were analyzed in the whole series and separately for primary or recurrent patients.

Crude cumulative incidence curves for each end point were calculated in a competing risks framework,²¹ and comparisons between curves in different subgroups were carried out by means of the Gray test.²² In the analysis of cause-specific mortality, deaths due to conditions unrelated with sarcoma were regarded as competing events. For local recurrence (distant metastasis) analysis, deaths without evidence of disease and distant metastasis (local recurrence), whichever occurred first, were regarded as competing events.

Multivariable analyses of each end point were based on cause-specific hazards and were therefore carried out using Cox multiple regression models. The analyses mainly focused on the prognostic effect of microscopic margin status. The following covariates, chosen before statistical analysis on the ground of literature information,^4-7,10 were included in the models for the purpose of adjustment: age, presentation (primary, recurrent), size, depth (superficial, deep), FNCLCC grade (I, II, III), location (proximal, distal), histotype (liposarcoma, synovial sarcoma, leiomyosarcoma, MPNST, MFH, vascular sarcoma, other sarcoma), and radiotherapy (yes, no). An exploratory analysis showed a prognostic effect of tumor size only among deeply located tumors. Consequently, the interaction term size x depth, but not the main effect of size, was entered into the models. Age and tumor size were modeled as continuous variables by using four-knot restricted cubic splines,²³ whereas the other covariates were modeled as categoric by using dummy (0/1) variables. To investigate the association between local relapse and cause-specific mortality, a Cox model was fitted with the inclusion of local relapse as an additional covariate. In such analysis, death-times were left-truncated at the time of local relapse occurrence. All of the above analyses were repeated with the inclusion of type of surgery, chemotherapy, and the year of surgery (to investigate possible period effects). As the estimates for the remaining covariates were negligibly affected, we only report the results of simpler models.

To check the proportional hazard assumption implied by the Cox model, we relied on the graphical analysis of scaled Schoenfeld residuals,²⁴ and on testing time-dependent covariates when deviations from the assumption were suspected.

We used SAS software (SAS Institute Inc, Cary, NC) and the S-Plus (StatSci; MathSoft, Seattle, WA) Design and Cmprsk (Harvard University, Cambridge, MA) libraries to perform the modeling and statistical calculations.²⁵ We considered as significant two-sided P values below the 5% conventional threshold.

	RESULTS

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Disease-Specific Mortality
Of the 911 investigated patients, 284 deaths were recorded. Of these, 237 (83%) were related to STSs and were thus considered in our analyses. Cause-specific deaths were 143 among the 642 primary cases and 94 among the 269 recurrent cases.

Five and 10-year mortality estimates were 0.24 (95% CI, 0.21 to 0.27) and 0.29 (95% CI, 0.26 to 0.32) in the whole series, 0.22 (95% CI, 0.18 to 0.25) and 0.25 (95% CI, 0.21 to 0.29) in the primary cases, and 0.28 (95% CI, 0.23 to 0.34) and 0.37 (95% CI, 0.31 to 0.44) in recurrences. This difference in outcome according to phase (primary versus recurrence) at presentation was statistically significant (P < .001).

In Figure 1, crude cumulative mortality curves are represented according to microscopic margin status. For primary cases (Fig 1A) 10-year estimates were 0.31 (95% CI, 0.20 to 0.42) in positive-margin cases and 0.24 (95% CI, 0.20 to 0.28) in negative-margin cases (P = .338). The corresponding figures in recurrent cases (Fig 1B) were 0.47 (95% CI, 0.34 to 0.59) and 0.34 (95% CI, 0.26 to 0.41); P = .019.

View larger version (11K): [in this window] [in a new window]   Fig 1. Cause-specific mortality by microscopic margin status in primary (A) and recurrent cases (B).

Local Recurrence
Two hundred twenty-six patients had local recurrence after surgery performed at our institute (129 with primary disease and 97 with local recurrence at presentation). One hundred fifty patients had only one local recurrence, while 76 had two or more local recurrences. Time to first local recurrence varied from 1 to 201 months, with the median time for those who recurred being 15 months. One hundred three patients had only local recurrence, while 123 had local recurrence and distant metastasis (the local recurrence anticipating the distant metastasis in 75 patients, being concurrent in 32 and posterior in 16).

One hundred seventy-eight local recurrences occurred as first events, of which there were 101 among primary tumors. Five-year and 10-year estimates were 0.17 (95% CI, 0.15 to 0.20) and 0.19 (95% CI, 0.17 to 0.22) in the whole series, 0.14 (95% CI, 0.11 to 0.17) and 0.15 (95% CI, 0.13 to 0.18) in the primary cases, and 0.25 (95% CI, 0.20 to 0.30) and 0.28 (95% CI, 0.23 to 0.34) in recurrences. This difference in local recurrence according to phase (primary v recurrence) at presentation was statistically significant (P < .001).

In Figure 2, crude cumulative incidence curves are represented according to microscopic margin status. For primary cases (Fig 2A), 10-year estimates were 0.29 (95% CI, 0.19 to 0.39) in positive-margin cases and 0.13 (95% CI, 0.10 to 0.16) in negative-margin cases (P < .001). The corresponding figures in recurrent cases (Fig 2B) were 0.34 (95% CI, 0.23 to 0.44) and 0.26 (95% CI, 0.20 to 0.32); P = .222.

View larger version (10K): [in this window] [in a new window]   Fig 2. Crude cumulative incidence of local recurrence by microscopic margin status in primary (A) and recurrent cases (B).

Distant Metastases
Two hundred seventy-nine patients had distant metastasis after surgery performed at our center (176 with primary disease and 103 with local recurrence at presentation). One hundred eighty-two patients had only pulmonary metastasis, 58 also developed extrapulmonary metastasis (11 patients before pulmonary metastasis, 28 concurrently to the lung, and 19 after), and 39 had only extrapulmonary metastasis. The site of extrapulmonary metastasis were the regional lymph nodes in 20 cases (14 of these died of disease), the skeleton in 18 cases, the soft tissues in 17 cases, the abdomen in 12 cases, the liver in nine cases, the brain in one case, and multiple organs in the remaining 20 cases. Time to distant metastasis varied from 1 to 213 months, with the median time for those who developed distant metastasis being 14 months. One hundred fifty-six patients had only distant metastasis, while 123 had also local recurrence, as reported above.

Two hundred four distant metastases occurred as first event (136 of these among primary tumors). Five and 10-year estimates were 0.21 (95% CI, 0.19 to 0.24) and 0.22 (95% CI, 0.20 to 0.25) in the whole series, 0.20 (95% CI, 0.17 to 0.23) and 0.21 (95% CI, 0.18 to 0.24) in the primary cases, and 0.25 (95% CI, 0.19 to 0.30) and 0.25 (95% CI, 0.20 to 0.30) in recurrences. This difference in distant metastasis according to phase (primary v recurrence) at presentation was not statistically significant (P = .174).

In Figure 3, crude cumulative incidence curves are represented according to microscopic margin status. For primary cases (Fig 3A), 10-year estimates were 0.23 (95% CI, 0.14 to 0.32) in positive-margin cases and 0.21 (95% CI, 0.17 to 0.24) in negative-margin cases (P = .450). The corresponding figures in recurrent cases (Fig 3B) were 0.31 (95% CI, 0.21 to 0.42) and 0.23 (95% CI, 0.17 to 0.29; P = .124).

View larger version (11K): [in this window] [in a new window]   Fig 3. Crude cumulative incidence of distant metastasis by microscopic margin status in primary (A) and recurrent cases (B).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
In this series of more than 900 patients with ESTSs who were surgically treated with an eradicating intent at our institution during a 20-year period, the cumulative incidences of local relapse and distant metastasis at 10 years were 19% and 22%, respectively. Disease-specific mortality at 10 years after definitive surgery was 29%. These results are superimposable to those reported in the main published series (Tables 5 and 6). ^{7,10,14,16,17} As expected, size of primary tumor, depth, malignancy grade, and histotype correlated with tumor recurrence, and consequently, with disease-specific mortality. The importance of quality of surgery seems more intriguing. In this series, poor surgical margins for primary tumors had some adverse effect, but this was major in terms of local control, and minor in terms of metastasis-free survival and cause-specific mortality, though it was visible to some extent in the proportion of patients who escaped an early relapse. In patients who were operated on for a local recurrence, the importance of surgical margins seems to be higher, as if the local recurrence selected a subgroup of patients for whom local control was more problematic, and thus more important for the final outcome.

Overall, however, while positive surgical margins adversely affected the local outcome, as shown both at univariable and multivariable analyses, distant metastasis and cause-specific mortality were only slightly different between the two groups of patients resected for a primary tumor with negative and positive margins, and this difference was not statistically significant at multivariable analysis. In other words, positive surgical margins may not be an independent factor, simply reflecting other problems inherent to the disease (eg, size, depth). Therefore, the same adverse prognostic factors would affect quality of surgery, local recurrence, and distant metastases.

In published literature, most studies failed to find a strong correlation between quality of surgery and final outcome. In both a series of 559 patients treated within the Scandinavian Sarcoma Group centers,¹⁴ and another series of 848 patients treated at The University of Texas M.D. Anderson Cancer Center,¹⁶ what was relevant for distant metastasis, and therefore disease-specific survival, was the intrinsic biologic aggressiveness of the tumor, as defined by size, depth, malignancy grade, and histotype.^4-7,11,17 In this sense, local recurrence might be well regarded as an additional biologic marker of aggressiveness (ie, a result rather than a cause). Under this interpretation, when a local recurrence is detected, the patient should be viewed as being at a higher risk of death due to factors inherent to his disease. Also, Lewis et al²⁶, in a series of 911 patients treated at Memorial Sloan-Kettering Cancer Center, found local that recurrence correlated with the development of subsequent metastases and tumor mortality, but concluded that local recurrence is not a source of metastasis, but rather a biologic phenomenon on the continuum of recurrent sarcoma. Some other smaller series showed that improved local control rates observed in patients with adequate surgical margins failed to translate into a survival benefit.^27-31 Furthermore, in the three published randomized trials^18-20 that compared more and less extensive local treatment modalities (amputation v conservative surgery + radiation therapy, or conservative surgery v conservative surgery + adjuvant radiation), differences in local outcome did not translate into differences in survival. The power of these randomized studies, however, is limited by the small sample size; therefore, no definitive conclusions can be drawn.

An important point should be taken into account when interpreting the lack of correlation between quality of surgical margins and final outcome. A strict application of Enneking criteria³² is precluded when analyzing large retrospective series, and the only possibility is to codify margins as either positive or negative. Indeed, the positive or negative status of the closest surgical margin is clearly a rough indicator of quality of surgery. Actually, some marginal excisions may well be included in the negative-margins group, thus contributing to confounding conclusions. Of course, the anatomic heterogeneity of adult STSs adds to these difficulties. It is probable that innovative definitions of quality of surgical margins (eg, based on width and type of surrounding healthy tissues, type of tumor margins, histotype, and grade) may help settle this highly controversial issue, and prospective clinical studies aimed at working out new definitions of adequacy of surgery would be welcome at this stage.

By contrast, in patients with an already locally recurrent tumor, the effect of surgical margins was more striking in our series. A distinct impact on metastasis-free and overall survival, as well as local control, was observed. One may believe that this patient population is selected in such a way that the local control is more important for them and may even have a prognostic impact. Clearly, however, patients in whom negative margins were not reached will have had worse prognostic factors locally. Therefore, we cannot conclude that a more aggressive local policy would have changed the final outcome. At any rate, it was just in this patient subgroup that receiving radiation therapy or not had prognostic relevance (and the choice to do radiation therapy or not, in this retrospective series, may have been less dependant on the local aggressiveness of disease). In brief, the hypothesis is that local recurrence defines a subgroup of patients for whom more aggressive local treatment might be worthwhile, though final proof thereof cannot be provided by this retrospective analysis.

In conclusion, microscopic residual disease may have an independent effect on disease-specific mortality, but this effect is minor. Indeed, a small proportion of patients (ie, those escaping early relapse due to inherent aggressiveness of disease) may suffer from inadequate surgery more clearly. Therefore, there are still good reasons to continue to pursue appropriate surgery in adult STSs (ie, clean margins at the very least; more sophisticated classifications of adequacy of margins would be welcome). On the other hand, when the clinical presentation is borderline; for example, when obtaining clean margins would require an amputation or major functional impairments, decision making may be reasonably flexible and shared with the patient, considering that his or her survival will directly depend only to a limited degree on quality of surgery itself. This may not apply to patients who have already had a local relapse. These patients seem to be selected in such a way that indicates that quality of margins is more important for them. In this subgroup of patients, therefore, to our knowledge, an attempt to reach an adequate local control might be especially crucial.

	Authors’ Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors’ Disclosures of... REFERENCES

 
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Submitted April 29, 2004; accepted October 1, 2004.

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