The objective of this study was to assess patient, tumor, and treatment factors that affected overall survival in a group of patients who underwent surgery for soft tissue sarcoma (STS) and presented with American Joint Commission on Cancer stage IV disease.
A retrospective review was undertaken of a single institution's database from the years 1986 to 2006 in all patients who met the following inclusion criteria: 1) surgical management of the primary tumor was undertaken, and 2) metastatic disease was present at the time of initial presentation. In total, 112 patients were identified who met the inclusion criteria.
The 5-year survival rate for the entire group was 17%. In univariate analysis, the variables that were identified as statistically significant for predicting improved overall survival were resection of metastatic disease (P = .003), <4 pulmonary metastases (P = .05), and the presence of lymph node metastases versus pulmonary metastases (P = .0002). In multivariate analysis, only the presence of lymph node metastases versus pulmonary metastases retained statistical significance (P = .05). The 5-year survival rate for patients who had lymph nodes metastases at diagnosis was 59%, whereas it was only 8% for patients who presented with pulmonary metastases.
Patients with soft tissue sarcoma (STS) who have metastatic disease at initial presentation generally have a very poor prognosis. However, there is a paucity of studies specifically addressing this clinical situation. One study based on the American Joint Committee on Cancer (AJCC) staging system for sarcoma1 indicated that patients who presented with metastatic disease (AJCC stage IV) had a 6% 5-year disease-specific survival rate.2 However, that investigation was part of a larger study and included patients with all stages of sarcoma, and it did not specifically address the treatment of patients as a factor that affected outcome.
There are several potential reasons why a surgeon may recommend resection of the primary tumor for a patient who presents with metastatic sarcoma. First, palliation of symptoms, such as pain in the extremity, may be more effective if the primary tumor is resected. Second, local surgery may be performed in the hope of prolonging life for a patient whose quality of life is reasonably good. Third, aggressive surgical treatment of the primary site and metastases may be recommended in the hope that a specific patient may be 1 of the few who is cured.
Currently, however, there are little data to suggest that surgical resection is effective in reaching any of these goals. In light of the significant demands on the patient, surgeon, and healthcare system entailed by the aggressive surgical management of sarcomas, it would be of significant benefit to provide evidence that this treatment recommendation is indeed advantageous.
The objective of the current study was to address the second and third potential reasons for recommending surgery described above: that is, undertaking the surgical management of patients who present with metastatic sarcoma in the hope of prolonging life or obtaining a cure. We sought to examine patient, tumor, and treatment factors as possible predictors of outcome in a group of patients who presented with metastatic sarcoma and underwent surgical resection of their primary tumors. Elucidation of these predictors potentially may allow surgeons to provide more accurate prognostic information to the patient and help guide treatment decisions. In addition, it may allow the more judicious use of surgical resection in this group of patients if surgeons are able to predict more accurately which patients are most likely to benefit, and patients who have an especially poor prognosis may elect not to undergo such extensive procedures if they have few or no symptoms and little chance of obtaining a cure.
MATERIALS AND METHODS
After approval from our institutional review board, a retrospective review was undertaken of our prospectively collected sarcoma database from the years 1986 to 2006. We identified all patients with STS of the extremities or trunk. Patients were included in the study if they 1) underwent definitive surgical resection of their primary sarcoma at our institution and 2) had evidence of metastatic sarcoma on systemic staging at the time of presentation (AJCC stage IV). The decision to undertake surgical resection was made after discussion at a multidisciplinary conference. In general, patients who had symptomatic tumors and who were deemed fit to undergo general anesthesia despite metastatic disease were offered surgical resection. Patients who had computed tomography (CT) scans of the chest that revealed questionable pulmonary metastases at diagnosis were included in the study group if a follow-up CT scan within 3 months of surgery revealed clear progression of pulmonary nodules. We assumed that the progression of pulmonary disease represented metastatic disease, and biopsies of pulmonary nodules generally were not undertaken. For patients who presented with lymph node metastases, needle or incisional biopsies generally were performed to confirm the diagnosis of regional metastatic disease. Patients who presented with local recurrence of sarcomas that previously were resected elsewhere were excluded.
From our database, we documented patient demographics, including age and sex; tumor features, including grade, size of the primary tumor, tumor depth relative to fascia, and histologic subtype; and location of metastases. The location of metastatic disease was classified as either lung or lymph nodes, and, if patients underwent resection of metastatic disease, we noted whether patients underwent either pulmonary metastasectomy or lymphadenectomy. Patients typically were offered pulmonary metastasectomy if the number of pulmonary metastases did not increase on short-term (ie, 3-month) follow-up CT scans and if the burden of pulmonary disease was small (ie, <4 metastases). For patients with pulmonary metastases, we documented the number and laterality of the pulmonary nodules. Finally, the use of radiotherapy or chemotherapy was noted. The decision to administer radiotherapy or chemotherapy was made on a case-by-case basis after discussion at a multidisciplinary conference that involved surgeons, radiation and medical oncologists, musculoskeletal radiologists, and pathologists. Patients who had sarcoma subtypes that typically are considered “chemosensitive,” such as synovial sarcoma and liposarcoma, often received chemotherapy in a neoadjuvant setting in an attempt to downstage their disease. Patients were considered for chemotherapy whether they had lymph node or pulmonary metastases.
We assessed all variables using log-rank tests to determine whether they were predictive of overall survival in Kaplan-Meier survival analysis.3 For patient, tumor, or treatment variables that were identified as significantly predictive of overall survival, we used a Cox proportional hazards analysis to determine which variables retained significance. Then, we evaluated the alternative outcomes of survival at 3 months and at 6 months. We compared these dichotomous outcomes using chi-square tests to determine which variables were associated with increased survival at these time points.
In total, 1537 patients underwent surgical resection for an extremity or trunk sarcoma at our institution during the years 1986 through 2006. Of these, 112 patients (7.3%) had metastases at presentation (AJCC stage IV disease). The mean age of these patients was 56 years (range, 15-93 years) at the time of presentation. There were 67 men and 45 women. At the time of analysis, 87 patients (78%) had died of metastatic sarcoma, 3 patients (3%) had died of unrelated causes, 6 patients (5%) were alive with disease, and 16 patients (14%) were alive without any evidence of disease. The 5-year estimated overall survival rate for the entire group was 17% (95% confidence interval [CI], 9%-25%) (Fig. 1).
In total, 88 patients (79%) presented with lung metastases, and 21 patients (19%) presented with lymph node metastases only. Three patients had both lung and lymph node metastases and, for the purposes of the current analyses, were included in the lung metastasis group. An additional 3 patients presented with bone metastases, which were identified on radiographs and magnetic resonance imaging scans after causing local symptoms. Patients typically did not undergo routine bone scans. The location of the lung lesions were documented in 86 of 88 patients who presented with lung metastases at diagnosis. Seventeen patients had unilateral lung metastases, and 69 patients had bilateral metastases. The number of pulmonary metastases on CT scans was documented in 86 patients. Thirty patients had ≤3 pulmonary metastases, and 56 patients had ≥3 pulmonary metastases. Information on pulmonary metastasectomy was available for 85 of 88 patients: Eighteen patients underwent resection of pulmonary metastases, whereas, in 67 patients, pulmonary metastasectomy was not undertaken. All 21 patients who had isolated lymph node metastases at presentation underwent lymphadenectomy. No patient with bone metastases underwent resection of metastatic disease.
Table 1 lists the tumor and treatment variables for the entire group. The majority of patients had tumors that were deep to fascia (89%), >5 cm in greatest dimension (86%), and high grade (83%). The majority of patients (87%) underwent limb salvage surgery, whereas only 13% of patients underwent extremity amputation. Sixty-two percent of patients received either preoperative or postoperative radiation, whereas 45% of patients received chemotherapy in either a neoadjuvant or adjuvant setting. Only 8 of 112 patients (7%) developed local recurrences. The most frequent anatomic primary tumor locations were the hip (28%), knee (25%), shoulder (16%), and elbow (12%). The most common subtypes of sarcoma were malignant fibrous histiocytoma (26%), synovial sarcoma (12%), leiomyosarcoma (12%), and malignant peripheral nerve sheath tumor (9%) (Table 2).
Table 1. Tumor and Treatment Characteristics
No. of Patients (%), n = 112
Table 2. Histologic Tumor Subtypes
No. of Patients (%), n = 112
Malignant fibrous histiocytoma
Malignant peripheral nerve sheath tumor
Alveolar soft part sarcoma
Clear cell sarcoma
Soft tissue Ewing sarcoma
Overall patient survival was compared for all variables of interest using the log-rank test. The variables that were not statistically significant in predicting overall survival were bilaterality of lung metastases (P = .96), receipt of chemotherapy (P = .15), anatomic location (P = .41), sex (P = .36), tumor grade (P = .3), tumor size <5 cm (P = .2), histologic subtype (P = .14), and depth to fascia (P = .08). The variables that were statistically significant on univariate analysis for predicting improved overall survival were resection of metastatic disease (P = .003), <4 pulmonary metastases (P = .05), and the presence of lymph node metastases versus pulmonary metastases (P = .0002). The 5-year estimated survival rate was 8% (95% CI, 2%-14%) for patients who presented with pulmonary metastases and 59% (95% CI, 37-81%) for patients who presented with lymph node metastases alone (Fig. 2). The median survival was 9 months for patients with pulmonary metastases and 30 months for patients with lymph node metastases. Of the 67 patients with lung metastases who did not undergo pulmonary metastasectomy, only 1 patient remained alive without disease at 36 months. This patient had synovial sarcoma and attained a complete response of pulmonary disease to neoadjuvant chemotherapy. Of the 18 patients with lung metastases who did undergo resection of metastatic disease, 4 patients remained alive without disease at 5 months, 73 months, 120 months, and 226 months of follow-up. At the time of the current analysis, 11 of 21 patients with lymph node metastases remained alive without disease at a mean follow-up of 59 months (range, 5-133 months).
The variables that demonstrated significance on univariate analysis were examined subsequently using a Cox proportional hazards model. The only variable that maintained statistical significance in the model was the presence of lymph node versus pulmonary metastases (P = .05; hazard ratio, 2.3).
In total, 26 of 112 patients survived for <3 months after diagnosis of their sarcoma, whereas 86 patients survived >3 months. Thirty-nine patients survived <6 months, and 73 patients survived >6 months. We could not identify any factor that predicted for survival longer than either 3 months or 6 months.
Several studies have examined predictors of outcome in patients with metastatic STS. Those investigations have revealed different patient, disease, and treatment factors that can be used for prognostic reasons. Although, in general, the outcome of patients with metastatic sarcoma is unfavorable, it is not uncommon for a small number of patients to be cured after very aggressive management.
Billingsley et al analyzed 230 patients who developed metastatic disease after treatment of localized STS.4 In multivariate analysis, those investigators determined that resection of all metastases, a disease-free interval >1 year, age <50 years, and the absence of local recurrence were associated with an increased likelihood of postmetastasis survival. In a larger series of 719 patients who either presented with or developed pulmonary metastases from STS, the same investigators demonstrated that resection of metastases, a disease-free interval >1 year, and low histologic tumor grade were associated with improved survival; whereas age >50 years and the histologic subtypes liposarcoma and malignant peripheral nerve sheath tumor were associated with decreased survival.5
Zagars et al examined a group of 402 patients with localized STS who developed recurrent disease after definitive treatment of their primary tumor.6 Among 285 patients in that study whose first recurrence was metastatic disease with or without concurrent local recurrence, a time to first metastasis >12 months, resection of metastatic disease, and the absence of previous chemotherapy for the primary tumor were associated with greater disease-specific survival.
Casson et al investigated the outcome of 58 patients who underwent pulmonary metastasectomy for STS7 and identified multiple factors that were associated with improved prognosis on univariate analysis, including <3 pulmonary nodules, unilateral pulmonary disease, longer doubling time of pulmonary nodule growth, and a histologic diagnosis of malignant fibrous histiocytoma. In multivariate analysis, however, only the number of pulmonary nodules detected on a preoperative CT scan maintained significance.
All of those previous studies either assessed patients who presented initially with localized disease and subsequently developed metastases or combined this group with patients who had metastases at presentation. Our study is unique in that it specifically addresses patients who had metastatic disease at presentation. The discrepancy in prognostic factors between our study and the previous studies is likely a result of this difference in presenting status. In our study, we assessed all factors that were identified as significant for predicting outcome in these previous studies, but we failed to demonstrate any statistical significance. Specifically, histologic grade, tumor depth, the receipt of chemotherapy, histologic subtype, and bilaterality of pulmonary metastases held no prognostic significance in our study. Consistent with the results reported by Casson et al,7 we also observed that having ≤3 pulmonary metastases portended a better prognosis, but, once again, this factor lost significance in multivariate analysis.
The only factor that we were able to identify as significant for predicting improved outcome in multivariate analysis was presentation with lymph node metastases rather than pulmonary metastases. This is consistent with previously published results by Riad et al,8 who reported that the 5-year estimated overall survival rate in 26 patients who were treated for STS and isolated lymph node metastases was 63%, which is similar to our current results. Those authors also observed that patients with isolated lymph node metastases had a prognosis similar to that of patients with AJCC stage III sarcoma and clearly superior to that of patients with pulmonary metastases. Other studies have reported 5-year survival rates after aggressive management of isolated lymph node metastases between 34% and 60%.9, 10 This finding of a superior prognosis for patients who present with lymph node metastases in our study and others supports the separation of lymph node metastases and pulmonary metastases in future staging systems for STS.
We failed to demonstrate any significant benefit for the use of chemotherapy in this patient group. Although only a small proportion of patients received chemotherapy, including a mix of patients who received either combined doxorubicin and ifosfamide or doxorubicin alone, the lack of improvement in overall survival is consistent with other large multicenter studies that assessed the utility of chemotherapy in patients with advanced sarcoma.11-13 Although we could not demonstrate any benefit in improving survival beyond 3 months or 6 months, in our study, we did not examine progression-free survival using the Kaplan-Meier method. The demonstration of a benefit in other larger randomized trials in improving progression-free survival suggests that the use of chemotherapy for this reason still may be valid.14 It remains unclear which chemotherapy regimen is superior: One large randomized trial suggested that the addition of ifosfamide added little benefit over single-agent doxorubicin in increasing progression-free survival.15 It is possible that there may be other benefits to chemotherapy that were not documented in this study, such as palliation of symptoms or shrinkage of the tumor, that may facilitate less extensive surgical resection. Therefore, the use of chemotherapy needs to be considered carefully in each patient based on factors like performance status, disease burden, and histologic subtype.16
Many histologic subtypes of sarcoma were included the current study, and the small number of patients in each group made statistical comparisons difficult. However, we did observe that the 5 patients with alveolar STS who presented with metastatic disease had a trend toward prolonged survival. This observation is consistent with that of Portera et al, who reported a median survival for patients with metastatic alveolar STS of 40 months and a 5-year overall survival rate of 20%.17
The other factors that approached statistical significance, including low tumor grade, resection of pulmonary metastases, and small tumor size, potentially could reach significance in a larger cohort of patients. Therefore, these factors could be used as surrogates for improved outcome and should be taken into consideration when deciding on aggressive management.
Surgical resection of STS is associated with a variable period of patient recovery. It is our experience that, depending on the size and extent of the tumor, recovery can fall somewhere between 3 months and 1 year.18 We also were interested in determining whether any factors that potentially affected overall survival also might be associated with the dichotomous outcomes of survival >3 months or >6 months. Determining these factors may help with the clinical decision of whether to offer surgery to patients who have a more limited life expectancy and, thus, might spend the majority of their remaining life recovering from surgery. For tumors that are asymptomatic, minimally symptomatic, or slow growing, local radiation19 or even follow-up alone may be a better alternative for patients who have a very poor prognosis. Although there is little literature on the subject, radiotherapy often is effective in controlling pain in patients with STS when it is used either as an adjuvant to surgery or as a solitary modality in the palliative setting.19 Unfortunately, we were unable to demonstrate that any of the examined tumor, patient, or treatment factors were predictive of survival beyond 3 months or 6 months. This is likely because the group as a whole was relatively homogenous on many of the factors: The majority of tumors were large, deep to fascia, and high grade.
The results of the current study underline the extremely poor prognosis for patients who present with metastatic sarcoma and particularly for those with pulmonary disease. Although the occasional patient may be cured after aggressive surgical management of both the primary tumor and pulmonary metastases, these patients are rare. In our group of 88 patients, only 16 patients had their lung metastases resected, and only 4 remained free of disease at the time of this report. Therefore, it is clear that, despite surgical resection of the primary tumor, which all of our patients underwent, the likelihood of a cure is small. Although the number of patients who underwent pulmonary metastasectomy was small, and it is difficult to draw a definitive conclusion about its effectiveness despite an apparent 25% success rate, it is likely that our series was biased, because all patients who had resectable pulmonary disease indeed underwent resection. This indicates that the only reliable factor a clinician can use to predict an improved chance of obtaining a cure is the presence of isolated lymph node metastases and subsequent resection of those metastases. Other factors, such as complete resection of metastatic disease and <4 pulmonary metastases, may be associated with a more prolonged survival, as suggested by other studies, but did not affect overall survival on multivariate analysis in the current study, which was limited to patients who had metastases at initial presentation.
Because our patients were selected to undergo surgery, it is quite likely that the results are biased toward a better outcome, because only those who were deemed fit for surgery were included. Patients with stage IV disease who are treated with pure palliative intent without surgery typically are followed by our palliative care service, and their survival statistics were not available for analysis. It is quite likely that their survival is poorer than the survival of patients who undergo surgery, but it would be difficult to conclude that surgery itself, rather than overall better patient condition, is the main contributing factor. Despite this preselection of fitter surgical candidates with metastatic disease, their poor outcome calls into question the goals of surgical management for these patients.
On the basis of these results, it is difficult to justify aggressive surgical resection with the primary objective of obtaining a cure if a patient with STS presents with pulmonary metastases. Although we did not examine progression-free survival, we attempted to examine this by assessing survival >3 months or >6 months. We could not identify any factor that predicted for survival >3 months or >6 months. Therefore, the objective of prolonging life does not appear to be a reasonable justification for undertaking aggressive surgery except possibly in healthy patients who are able to accept and tolerate the morbidity of surgery for both the primary and metastatic sites with or without additional chemotherapy. The use of radiotherapy in this setting also is debatable, because local recurrence after surgery may not be an issue before patients die from their metastatic disease. However, radiation may be useful in an attempt to initially palliate symptoms19 while allowing time for documentation of the rate of metastatic progression.
It may be best to consider palliative treatment for patients who present with pulmonary metastases. Therefore, any treatment that is undertaken should have a goal of improving the patient's quality of life. In some circumstances, this still may be a viable reason for aggressive surgical management. Occasionally, palliative surgery can produce significant relief of local symptoms, particularly pain, in properly selected patients.20, 21 However, formal evaluations of quality-of-life outcomes are infrequent. An assessment of the literature on decision making for palliative surgery revealed that only 17% of studies on palliative cancer surgery assessed quality-of-life issues; and, of those, only 40% used a validated research tool, most often the Karnofsky performance scale.22 Other outcomes that more broadly assess the multifactorial effect of cancer on quality of life, including the Functional Assessment of Cancer Therapy,23 the Functional Living Index-Cancer,24 and the Edmonton Symptom Assessment System,25 rarely were used,22 highlighting the limited evidence on which to base recommendations for aggressive surgical management in the palliative setting.
Data on palliative surgery for sarcoma are limited even further. The diagnosis of sarcoma often is grouped with other rare cancers in a heterogeneous mix in quality-of-life outcome studies,22 which further limits the ability of investigators to effectively use the results in clinical decision making. Even the few studies that have addressed outcomes after palliative surgery that included sarcoma featured extremity amputations26 rather than outcomes after the more standard limb salvage surgery that is performed currently. These studies suggested an improved quality of life for properly selected patients who underwent amputation, which may justify the relatively high amputation rate in that series.26
In summary, patients who present with metastatic soft tissue sarcoma generally have an extremely poor prognosis regardless of the treatment they receive. Patients who present with isolated lymph node metastases should be considered potentially curable and should be managed with aggressive surgical resection of the primary tumor and metastasis. The objective of management for most patients who present with pulmonary metastases is less clear, because the likelihood of achieving a cure is much more remote. Consideration should be given to enrolling patients in clinical trials or commencing chemotherapy with the goal of symptom palliation.19 In those who respond, ie, develop shrinkage of their primary tumor and/or stabilization of pulmonary disease, further discussion may be undertaken with the patient regarding the role of aggressive local management using surgery with or without radiation along with management of the pulmonary disease. Further evaluation of the role of aggressive surgery in improving quality of life for patients who present with metastatic sarcoma is warranted.