Introduction

Soft tissue sarcoma (STS) encompasses an anatomically and histologically diverse group of neoplasms, most of which arise from mesodermal origin. These neoplasms are rare with approximately 7000 cases and 4300 deaths per year in the United States (1). Complete surgical resection is the cornerstone of treatment and prognosis is associated with tumor size, depth, histologic grade and anatomic site of the primary lesion (2). Retroperitoneal/visceral (RP/V) sarcoma has a worse prognosis than extremity/trunk (E/T) lesions, and this is likely due to its frequent presentation with large size precluding complete surgical resection (3). Multimodality therapy with adjuvant radiation has been shown to improve local control in resected high risk extremity sarcoma (4, 5), but toxicity to adjacent organs limits the delivery of adequate dose radiation therapy to the tumor bed after resection of most RP/V tumors. The data on the usefulness of adjuvant chemotherapy for high risk STS is conflicting, but a meta-analysis of the published literature suggests a marginal benefit in disease-specific survival, but not overall survival (6). Most histologic subtypes have the capacity to spread hemato-genously and regional lymph node metas- tases are rare. Pulmonary metastasis is the most common site of distant failure, but complete surgical resection of pulmonary metastasis has resulted in long term survival in select patients (7).

Etiology, epidemiology and genetics

Most STS patients have no identifiable exposure to an etiologic agent. Some have suggested that a history of previous local trauma predisposes to the development of STS, but this has been refuted by others and remains unproven. Radiation associated sarcoma has been seen in patients with a history of ionizing radiation therapy, but this is a relatively rare occurrence and represents only a small fraction of STS patients. In addition, lymphangiosarcoma has been associated with chronic lymphedema in patients who have had axillary surgery and radiation for breast cancer (Stewart-Treves syndrome).

Certain genetic diseases such as the Li-Fraumeni syndrome and neurofibromatosis have been associated with hereditary STS. In addition, unique tumor-specific genetic translocations have been identified in certain subtypes of STS (e.g., synovial cell, desmoplastic round cell, primitive neuro-ectodermal tumor, alveolar rhabdomysarcoma, myxoid chondrosarcoma and myxoid liposarcoma). The clinical significance of these tumor-specific genetic alterations continues to be studied, but, currently, molecular genetics can be used diagnostically to identify tumor-specific gene translocations in certain types of STS when histology is non-diagnostic or uncertain (8, 9).

Pathology, clinical presentation and staging

Figure 1 shows the anatomic distribution of 3796 patients treated for STS at Memorial Sloan-Kettering Cancer Center from 1982–1998. The clinical significance of the various subclassifications are minimal as histologic grade, not subtype, is the predominant determinant of recurrence and prognosis. Figure 2 shows the site-specific histologic subtype of these patients. Liposarcoma and malignant fibrous histiosarcoma (MFH) are the most common E/T lesions and liposarcoma and leiomyosarcoma are the most common histologies seen in RP/V sarcoma. Patients with E/T lesions usually present with a painless mass, but for RP/V sarcoma tumors often grow to massive sizes before recognized, usually presenting with abdominal distension, a palpable mass or gastrointestinal symptoms.

Figure 1

Figure 2

The American Joint Committee on Cancer (AJCC) staging system for sarcoma is unique in that sarcoma is the only solid tumor which incorporates histologic grade into its staging. Size, depth and grade are independent prognostic factors and large, deep, high grade lesions are associated with higher recurrence and death rates (10). Prognostic variables for both E/T and RP/V sarcoma have been evaluated using multivariate analysis of a large, prospective database maintained at our institution (3, 11) and they are shown in table I.

Table I

Independent prognostic variables in resected extremity/trunk and retroperitoneal/visceral STS from the MSKCC prospective database.

Treatment of localized STS

Surgery remains the primary effective treatment for localized STS and complete resection with maximal preservation of function is the objective of the sarcoma surgeon. In extremity sarcoma, the development of multimodality therapy using adjuvant radiotherapy has allowed for equally effective treatment strategies that utilize less radical, limb-sparing, surgical resections. In a landmark randomized trial performed at the National Cancer Institute (NCI) patients with extremity sarcoma were randomized to receive limb-sparing surgery plus post-operative radiation therapy or amputation (12). Both arms of the trial included doxorubicin based chemotherapy. Although local recurrence was higher in the limb-sparing group, the overall survival was identical between the two groups. Therefore, for patients with a limb-sparing option, multimodality therapy with local resection and adjuvant radiation therapy is preferable, and amputation for extremity STS is rarely performed. Subsequent randomized trials comparing adjuvant radiation after limb sparing surgery to surgery alone have shown that the addition of radiation by the BRT technique significantly improves local control in patients with high grade extremity tumors, but does not have an effect on disease-specific survival (4) (table II). Although a benefit in local control was not seen for patients with low grade tumors in the BRT trial, the NCI randomized trial of adjuvant EBRT did show a statistically significant improvement in local control for both high grade and low grade extremity STS. Again, there was no difference in disease-specific survival between the treatment and the observation group.

Table II

Randomized trials of surgery alone vs. adjuvant radiation therapy in extremity STS.

Unfortunately, similar strategies using adjuvant radiation for RP/V tumors has been limited by the toxicity to adjacent organs which prevents the delivery of adequate doses of radiation to the tumor bed. In an analysis of 500 patients treated for retroperitoneal sarcoma at our institution, of 278 patients presenting with primary, non-recurrent retroperitoneal sarcoma 231 (85%) were resectable and of these, 185 (80%) had complete surgical resection with gross negative margins. Resection of contiguous organs was performed in 77% of resected patients (3). A randomized study comparing intra-operative radiation therapy (IORT) to external beam (EBRT) in retroperitoneal sarcoma has been performed. This trial did show improved local control in the IORT group, but no difference in overall or disease-specific survival. In addition, the high incidence of neurotoxicity in the IORT group (47%) is concerning (13). Many non-randomized studies of IORT have been reported, but given the heterogeneity of the tumors treated and the varied regimens and doses delivered, it is difficult to interpret this data and IORT for retroperitoneal sarcoma should be considered experimental.

Table II summarizes the two published randomized trials of adjuvant radiation therapy in extremity sarcoma. For patients with high grade E/T lesions, both studies showed improved local control but no survival advantage with adjuvant radiation delivered either by external beam in the NCI trial or by brachytherapy (BRT) in the MSKCC trial. Preliminary results of the Canadian Sarcoma Group randomized trial comparing adjuvant brachytherapy vs. external beam have been reported and this study will likely show no difference in local control between the two methods. Advocates of brachytherapy would argue that the treatment can be completed during the immediate post-operative period, whereas EBRT must be delivered over a longer period of time, typically six weeks.

Figure 3 shows current management algorithms for E/T and RP/V sarcoma at our institution. These treatment strategies are based on our analysis of prognostic factors and the selection of patients at high risk for recurrence who are treated with multi-modality therapy. The 5 year disease specific survival in all patients treated at MSKCC from 1982–1998 (n = 3796) is 67% for E/T lesions and 38% for RP/V sarcoma.

Figure 3

Treatment algorithm for STS at MSKCC.

Adjuvant chemotherapy for STS remains investigational as several randomized clinical trials have been unable to show a consistent benefit. Table III summarizes the previously conducted randomized trials all of which have tested doxorubicin based regimens. The Sarcoma Meta-analysis Collaboration recently published a meta-analysis of all randomized trials (published and unpublished) of doxorubicin-based adjuvant therapy for STS (6). This study showed a marginally improved local recurrence-free survival and distant recurrence-free survival in the treated group, but no statistically significant improvement in overall survival. In addition, a large single institution retrospective comparison of pre-operative vs. post-operative doxorubicin based chemotherapy showed no difference in local recurrence free survival, disease-specific survival or overall survival (14). Based on these results adjuvant chemotherapy for soft tissue sarcoma should be considered experimental and delivered in the context of a clinical trial.

Table III

Prospective randomized trials of adjuvant chemotherapy vs. observation in extremity STS.

Hyperthermic isolated limb perfusion (HILP) is an investigational technique that has been used in a subset of patients with extremity STS. This method has been used mainly for patients with advanced local disease or in transit extremity metastases in order to attempt limb salvage in these patients who would otherwise require amputation. The largest experience in this technique is reported in a multicenter phase-II-trial in which 55 patients were treated with HILP using high dose tumor necrosis factor-α, interferon-γ and melphalan (15). A limb salvage rate of 85% is reported in this study with a complete pathologic response seen in 36%.

Treatment of local recurrence

The management of local recurrence can be problematic and treatment must be individualized depending on the previous treatment received and the anatomic site of local recurrence. For patients with isolated local recurrence of E/T lesions, re-resection is usually warranted and longterm limb salvage rates of 67% have been reported after re-resection of E/T recurrences (16). The incidence of LR is much higher for patients with RP/V primaries, mainly due to the large size of these tumors and the inability to deliver adequate adjuvant radiation therapy to the post-resection tumor bed.

In a series from our institution of 231 patients who underwent resection for primary retroperitoneal sarcoma, 41% had developed local recurrence by 5 years. Subsequent survival is strongly associated with complete re-resection, and the 5 year DSS after complete gross re-resection is similar to that after primary resection. In patients who had incomplete resection of their RP local recurrence, no benefit in survival was seen when compared with unresectable patients who were treated with observation alone. Excluding palliative resection for patients with symptomatic local recurrence, re-operation should be considered only when complete gross resection is possible (3).

Surgical treatment of metastatic STS

The results of surgical therapy for pulmonary metastasis from STS has been reported by several groups (7, 17–19). Careful patient selection is critical and only patients who have pulmonary metastasis amenable to complete resection, have no evidence of extra-thoracic disease and who are medically fit enough to tolerate a thoracotomy and resection should be considered. No randomized trial comparing surgery to observation or systemic therapy has been performed, but in several series the 5 year survival rate has been reported to be 20–40% which is better than expected when compared to historical controls treated with chemotherapy or observation.

In a large, recently updated series from our institution, patients treated with complete resection had a median survival of 33 months and a 3 year actuarial survival of 46% (7). This appears markedly improved from our previously reported 3 year survival of 23% (20) and this is likely due to better patient selection, and shorter follow-up with actuarial survival projection. Similar results were seen in a multi-center European trial in which disease-free post-metastectomy survival rates were 42% at three years and 35% at five years (21). In both studies, a long diseasefree interval and complete resection were the most powerful favorable prognostic indicators, underscoring the fact that careful patient selection is critical.

Summary

STS comprises a heterogeneous and diverse group of neoplasms. Surgical resection is the only known curative treatment and for patients with high grade extremity tumors, multi-modality therapy with surgery and radiation therapy has been shown to improve outcome in several randomized trials. Radiation therapy in E/T lesions can be delivered by either external beam or brachytherapy and no difference in efficacy between the two methods can be demonstrated in clinical trials.

For RP/V tumors, local recurrence remains problematic, as complete surgical resection is often impossible and adjuvant radiation therapy is difficult to deliver because of dose-limiting toxicity to surrounding organs in the often very large tumor bed. Retroperitoneal STS often recurs locally and local recurrence alone in the absence of distant recurrence can cause death. Conversely, for visceral sarcoma, hematogenous spread to the liver is often encountered in conjunction with local recurrence precluding re-resection with curative intent. Since many patients with RP/V sarcoma can die with local disease only, improvements in local control should translate into improvements in DSS. Controlled trials using IORT and phase-I-trials of intra-peritoneal chemotherapy have not shown improvements in survival and these modalities remain experimental at present.

For the biologically distinct subset of patients who recur with isolated distant metastasis, surgical resection of pulmonary metastasis has shown a survival benefit when compared with historical controls. Given the significantly improved survival compared to untreated patients, it is unlikely that a randomized trial of resection vs. observation will ever be conducted. Because of the high risk of recurrence after pulmonary resection for metastasis, trials of adjuvant chemotherapy and immunotherapy in this cohort of patients should be of high priority.

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