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© 2003 American Society for Clinical Oncology Synovial Sarcoma of Childhood and Adolescence: A Multicenter, Multivariate Analysis of OutcomeFrom The University of Texas M.D. Anderson Cancer Center, Houston, TX; the Olgahospital, Stuttgart, Germany; St. Jude Children’s Research Hospital, Memphis, TN; and Istituto Nazionale dei Tumori, Milan, Italy Address reprint requests to Mehmet Fatih Okcu, MD, MPH, Baylor College of Medicine, Texas Children’s Cancer Center, 6621 Fannin, CC 1510.00, Houston, TX 77030-2399; email: mfokcu{at}txccc.org.
Purpose: To identify prognostic factors related to outcome in 219 children and adolescents with synovial sarcoma. Patients and Methods: We combined the experiences of the four following research groups: Cooperative Weichteilsarkomastudie Group, Germany (n = 95); St. Jude Children’s Research Hospital, Memphis, TN (n = 49); Istituto Nazionale dei Tumori, Milan, Italy (n = 33); and The University of Texas M.D. Anderson Cancer Center, Houston, TX (n = 42). Kaplan-Meier and Cox proportional hazard analyses were performed. Results: The median age at diagnosis was 13 years (range, 1 to 20 years), and the median follow-up was 6.6 years (range, 0.5 to 30.7 years). The estimated 5-year overall survival and event-free survival rates for the entire group were 80% ± 3% (SE) and 72% ± 3%, respectively. A previously unreported interaction between tumor size and invasiveness was observed that statistically significantly related to outcome. In multivarible analysis, patients with T1B and T2B disease (hazard ratio [HR] = 5.6, 95% confidence interval (CI), 1.9 to 16.2; and HR = 5.9, 95% CI, 2.1 to 16.4, respectively) or Intergroup Rhabdomyosarcoma Study (IRS) Clinical Group III and IV disease (HR = 2.7, 95% CI, 1.2 to 6.5; and HR = 14.1, 95% CI, 4.3 to 31.3, respectively) had poor overall survival. Treatment with radiotherapy was related to improved overall survival (HR = 0.4; 95% CI, 0.2 to 0.7). In IRS Group III patients, objective response to chemotherapy (18 of 30, 60%) correlated with improved survival. Conclusion: Clinical group, tumor size, and invasiveness are important prognostic factors. Multicenter randomized clinical trials are needed to determine both the effect of chemotherapy on survival and the necessity of local radiotherapy in patients with completely resected tumors.
SYNOVIAL SARCOMA (SS) is the most common nonrhabdomyosarcomatous childhood soft-tissue sarcoma, with an annual incidence rate in the United States of 0.7 per million in children and adolescents younger than 20 years of age.1 The median age of patients at diagnosis is in the third decade of life, with 31% of the cases being in adolescents younger than 20 years of age.2 The disease is unique in its differentiation into two elements: epithelial cells with glandular components and spindle cells.2 SS arises in the para-articular regions, mainly in the tendons, tendon sheaths, bursal structures, and less frequently, in the fascial structures and ligaments.3 The most common site of metastasis is the lung; however, unlike most other nonrhabdomyosarcomatous soft-tissue sarcomas, SS can also spread to regional lymph nodes.4 Despite numerous case reports and several relatively large case series, controversy still exists about the prognostic factors for the disease and whether adjuvant chemotherapy is useful in treating patients. To explore the relationships between clinicopathologic features at diagnosis, treatment, and outcome, we conducted a retrospective, multicenter multivariate analysis in 219 children and adolescents diagnosed with SS.
Patients and Clinicopathologic Characteristics A total of 219 children and adolescents were diagnosed between 1966 and 1999; follow-up was updated in April 2001. The research groups, which had already published their experience for a subgroup of their case patients, included in this article are as follows: German Cooperative Weichteilsarkomastudie (CWS) Group (n = 95; St. Anna Children’s Hospital, Vienna, Austria; the Olgahospital, Stuttgart, Germany; the University Children’s Hospital, Munster, Germany);5 St. Jude Children’s Research Hospital (n = 49);6 Istituto Nazionale dei Tumori (INT), Milan, Italy (n = 33);7 and the University of Texas M.D. Anderson Cancer Center (MDACC; n = 42).8 All of the pathology slides were evaluated, and the diagnosis of SS was confirmed at each institute at the time of diagnosis. Tumors were classified as biphasic, monophasic, or poorly differentiated by histology (as previously described)2 in all but two of the 219 evaluable patients. Information on age at diagnosis, date of diagnosis, sex, race, clinical group,9 details of therapy, and clinical outcome were available in all patients. Duration of follow-up was calculated in all but one patient. Information on exact tumor size was available for 194 patients, on primary site for 202 patients, and on tumor invasiveness (based on the tumor-node-metastasis ([TNM] system) for 215 patients.10
Clinical group was determined according to the surgicopathologic staging system of the Intergroup Rhabdomyosarcoma Study (IRS). In brief, patients with group I disease had localized completely resected tumors, group II patients had microscopic residual disease with or without resected tumor-involved regional lymph nodes, group III patients had gross residual tumor after surgery, and group IV patients had distant metastases at the time of diagnosis.9 Information on tumor invasiveness (based on the TNM system) was obtained from operative notes and radiologic imaging and pathology reports.10 In the TNM system, T1 lesions are confined to the organ or tissue of origin and are further subdivided by maximum diameter (< 5 cm, T1A; Altogether, 131 patients (60%) received local radiotherapy with total doses ranging from 16 to 68 Gy, with a median dose of 50 Gy. One hundred seventy-nine patients (84%) were treated with various chemotherapy regimens, with or without radiotherapy. Of those patients treated with chemotherapy, 151 (84%) received doxorubicin with an alkylating agent (cyclophosphamide, n = 88, 49%; ifosfamide, n = 57, 32%; and dacarbazine, n = 6, 3%); 16 patients (9%) were treated with an alkylating agent without doxorubicin; and the remaining 12 patients (7%) were treated with other chemotherapy combinations. To compare the efficacy of various chemotherapy combinations, regimens were classified into the following groups for two separate analyses: first analysis, alkylating agent and doxorubicin (n = 151), alkylating agent without doxorubicin (n = 16), and all others (n = 12; no patients were treated with a regimen that contained doxorubicin without an alkylating agent); and second analysis, ifosfamide and doxorubicin (n = 57), other alkylating agent and doxorubicin (n = 94), other alkylating agent without doxorubicin (n = 16), and all others (n = 12). We evaluated the importance of degree of response to chemotherapy by correlating response with survival and progression or recurrence in 30 of the 45 IRS Group III patients for whom such information was available. With the exception of a subgroup of the CWS cases, in all patients, response to chemotherapy was grouped into one of the following three categories: complete response (CR) or more than 50% partial response (PR); more than 25% but less than 50% objective response (OR); or less than 25% response, no response, or progressive disease. In CWS cases, patients with an objective reduction in their tumors of more than 33% but less than 67% of the initial size were classified as having a good response. These analyses were performed twice. The CWS subgroup was first analyzed with the more than 50% PR group and then it was analyzed with the less than 50% OR group. Because improvements in radiologic techniques and supportive care may have influenced diagnosis and outcome, treatment era was assessed as a variable in the analyses for three periods: 1960s and 1970s combined, 1980s, and 1990s.
Statistical Methods
To adjust the regression model for differences among the study centers, the study-center variable remained in the model in all analyses. Age at diagnosis was used as a continuous variable, whereas all other variables were used as categorical variables as shown in the tables. We calculated the HR and its associated 95% CIs for each variable that remained in the model. Either
Patient Characteristics Patient demographics and clinical characteristics are shown in Table 1  . The median age at time of diagnosis was 13 years (range, 1 to 20 years). Only eight patients (4%) were older than 18 years at diagnosis. There were 115 males (53%), and 191 patients (87%) were white. The most common site for the primary tumor was the lower extremity (n = 135, 62%). Ninety-three patients (42%) had IRS group I disease; 66 patients had IRS group II disease (30%), and 45 patients had IRS group III disease (21%). Of the 219 evaluable patients, 100 (46%) had invasive disease. A total of 101 patients (46%) had tumors less than 5 cm in diameter, and 58 patients (27%) had tumors between 5 and 10 cm in diameter. Thirty-five patients (16%) were treated from 1960 through 1979, 89 patients (41%) were treated from 1980 through 1989, and 95 patients (43%) were treated in 1990 or later. Eighteen patients (8%) had surgery only, 69 patients (32%) had surgery and chemotherapy, 22 patients (10%) had surgery and radiation therapy, and 109 patients (50%) had a combination of all three therapeutic modalities.
Overall Survival The median follow-up time was 6.6 years (range, 0.5 to 30.7 years). For the 165 patients (75%) alive at last follow-up, the median time after diagnosis was 7.5 years (range, 0.9 to 30.7 years); only two patients were followed up for < 2 years. A total of 54 patients (25%) died; 47 from progression or recurrence, two from immediate adverse effects of SS therapy, two after developing osteosarcoma in the radiation field, and three from causes unrelated to cancer. Twenty-two patients (10%) had relapsed but were still alive. The estimated 5-year OS for the entire group was 80% ± 3% (± SE; Fig 1 ). Table 2 shows 5-year OS estimates for variables that are statistically significant in multivariable analyses. Race, tumor size regardless of invasiveness, radiotherapy, IRS group, and treatment era were statistically significantly associated with OS in the univariate analyses. However, in the multivariable analyses, older age at diagnosis, tumor size regardless of invasiveness (T1B and T2B), lack of radiotherapy, and advanced disease (ie, IRS groups III and IV) were the only statistically significant prognostic factors associated with poor survival. With every 1-year increase in age, risk of dying from SS increased 0.07 times.
Event-Free Survival Seventy-six (35%) patients experienced one or more events. First events consisted of 19 (25%) local recurrences, 35 (46%) distant recurrences, 15 (20%) combined local and distant recurrences, two occurrences of osteosarcoma within the radiation field, two deaths related to therapy, and three deaths unrelated to cancer. The estimated 5-year EFS for the entire group was 72% ± 3% (Fig 1  ). Five-year EFS estimates for variables that were statistically significant in multivariable analyses appear in Table 3. In the univariate analyses, race, age at diagnosis, tumor size regardless of invasiveness (Fig 2), radiotherapy, and IRS group were all statistically significantly associated with EFS. In the multivariable analyses, tumor size regardless of invasiveness (T1B and T2B), lack of radiotherapy, monophasic histology, head and neck as primary site, and presence of metastases at diagnosis (ie, IRS group IV) were all statistically significantly associated with worse outcome. Older age at diagnosis was associated with poor EFS; with every 1-year increase in age, risk of having an event increased 0.06 times.
Patients With Grossly Resected Tumors (IRS Groups I and II) OS and EFS were similar for patients for which complete resection of the tumors (with or without microscopic residual) was accomplished before adjuvant therapy (Tables 2 and 3). Tumor invasiveness and size were statistically significantly associated with OS and EFS in univariate and multivariable analyses. Compared with patients with T1A disease (5-year EFS and OS, 95% ± 3% and 99% ± 2%, respectively), patients with T1B disease were 3.1 times (95% CI, 1.2 to 8.2) and 4.8 times (95% CI, 1.2 to 18.7) more likely to progress or die from SS, respectively (5-year EFS and OS, 76% ± 8% and 86% ± 7%, respectively). Similarly, patients with T2B disease were 10 times (95% CI, 4.1 to 24) and 12.7 times (95% CI, 3.6 to 45.3) more likely to progress or die from SS, respectively (5-year EFS and OS, 43% ± 9% and 61% ± 9%, respectively). Five-year EFS and OS for T2A patients was 92% ± 6% and 96% ± 4%, respectively. Patients treated with radiotherapy were 0.65 times (95% CI, 0.35 to 1.2) less likely to progress (5-year EFS, 83% ± 4%) and 0.6 times (95% CI, 0.28 to 1.3) less likely to die from SS (5-year OS, 91% ± 3%) compared with those not treated with radiotherapy (5-year EFS and OS, 73% ± 6% and 83% ± 5%, respectively).
Patients With Gross Residual Disease after Primary Surgery (IRS Group III)
Patients With Distant Metastatic Disease at Diagnosis (IRS Group IV)
Local Radiotherapy and Chemotherapy
Response to Chemotherapy Evaluation of OR determined by radiography was available for 30 (71%) of the 42 IRS group III patients treated with chemotherapy. Two of the 11 patients with CR/PR and two of the seven patients with OR had unfavorable events (overall, 4 of 18 patients; 22%). By contrast, seven (58%) of the 12 patients who had no response or progression, ultimately failed (P = .06). Similarly, two of the 11 patients with CR/PR and none of the seven patients with OR died (overall, 2 of 18 patients, 11%), whereas five of the 12 (42%) patients in the no response/progression group died (P = .08). These results did not change significantly when three CWS patients who were reported to have had a reduction of more than 33% but less than 67% of the initial size of their tumors after chemotherapy were included in either the CR/PR or the OR groups. Two patients who achieved a CR with chemotherapy only were also treated with local radiotherapy without any subsequent surgery; these patients are alive with no evidence of SS at 4.9 and 7.6 years after diagnosis.
Local Recurrence
Overall, 34 patients (34 of 219 patients; 16%), including those in IRS group IV, developed a local recurrence (15 patients had a simultaneous distant recurrence), with a median time to the local recurrence of 1.3 years (range, 0.1 to 20.3 years). Of those 204 patients with localized disease (IRS groups I-III), 27 (13%) developed a local recurrence (eight had a simultaneous distant recurrence), with a median time to local recurrence of 2 years (range, 0.2 to 20.3 years). In eight patients, local recurrence was noted more than 5 years after initial diagnosis. The estimated 5-year local recurrence-free rate was 87% ± 2%. Table 5
IRS group III patients who were treated with local radiotherapy had a 5-year local recurrence-free survival of 96% ± 4%, whereas the 5-year local recurrence-free survival for those not treated with radiotherapy was only 50% ± 15% (P = .01). In IRS group I and II patients, no statistically significant difference was found between patients who received radiotherapy and those who did not (5-year local recurrence-free survival, 96% ± 2% v 87% ± 5%, respectively, P = .12). In the univariate analysis of IRS group I and II patients, patients with T2B disease were 4.6 times (95% CI, 1.3 to 16.5) more likely to experience a local recurrence (5-year local recurrence-free survival, 85% ± 7%) than were patients with T1A disease (5-year local recurrence-free survival, 97% ± 2%). The multivariable analysis, however, did not reveal a statistically significant association with local recurrence in IRS groups I and II combined or in IRS group III alone.
Distant Recurrence
Overall, 50 of the 219 evaluable patients (23%) had a distant recurrence as the first event (15 had a simultaneous local recurrence), with a median time to distant recurrence of 1.6 years (range, 0.1 to 9 years, with six of these events occurring 5 years after diagnosis and two occurring simultaneously with a local recurrence). Of 204 patients with IRS group I-III disease, 37 (18%) had a distant recurrence with a median time to distant recurrence of 1.2 years (range, 0.1 to 9.0 years). The estimated 5-year distant recurrence-free rate was 79% ± 3%. Table 6
In patients with grossly resected tumors (ie, IRS groups I and II), tumor size combined with invasiveness was statistically significantly associated with occurrence of distant recurrence in multivariable analysis. Patients with T2B tumors (5-year distant recurrence-free survival, 48% ± 9%) were 63.5 (95% CI, 8.1 to 496.9) times more likely to have a distant recurrence than were patients with T1A and T2A disease (5-year distant recurrence-free survival, 100% and 96% ± 4%, respectively). Similarly, the risk of a distant recurrence for patients with T1B tumors (5-year distant recurrence-free survival rate, 85% ± 7%) was 16.6 (95% CI, 1.9 to 144) times higher than patients with T1A and T2A disease. In univariate or multivariable analyses, no variable, including tumor size and invasiveness, was statistically significantly associated with occurrence of distant recurrence in patients with IRS group III disease.
Survival After Recurrence
The four previously published articles exploring prognostic factors associated with outcome in children and adolescents with SS, which included most of the patients in this study, found that IRS grouping,5,6,8 tumor invasiveness,6–8 tumor size,5,6,8 and histologic grade6 were all statistically significantly associated with outcome in both univariate and bivariate analyses. The analyses presented in this study confirmed that the first three variables are statistically significantly related to outcome. Moreover, we were able to identify a previously unreported interaction between tumor size and invasiveness, which has a significant effect on outcome. We did not have histologic information on tumor grade in the majority of patients; thus, this important feature should be incorporated into future trials to investigate its role in outcome in patients with SS. In similar studies involving adults with SS, advanced stage and large tumor size (  5 cm) have been consistently identified as poor prognostic factors.14–18 High mitotic index, tumor invasion, and presence of microscopic residual disease after surgical resection have also been significantly associated with poor outcome.16,17,19,20 Recently, the presence of the SYT-SSX2 fusion gene was significantly associated with better survival in 243 adult patients with localized disease;18 treatment and invasiveness were not, however, included in that analysis. In our analyses, the most consistent statistically significant variable associated with poor outcome was tumor invasiveness combined with tumor size. The estimated 5-year survival rates were highest and most similar in patients classified with T1A and T2A tumors compared with patients with T1B and T2B disease. Moreover, in the analyses in which tumor size combined with invasiveness was a statistically significant prognostic variable, T2B patients had worse outcomes than did T1B patients. This finding indicates that local invasion of bone and vascular tissues by the tumor is not in itself important for prognosis in tumors smaller than 5 cm. However, patients who had invasive tumors larger than 5 cm had worse outcomes. These findings indicate a strong synergistic interaction between tumor size and invasiveness. This interaction was most apparent in IRS group I and II patients; the HRs for developing distant recurrence were unexpectedly high for the patients with T1B disease and much higher for the patients with T2B disease compared with T1A and T2A patients. The second most common prognostic factor associated with poor outcome in our study was absence of local radiotherapy. In the overall series analyses, the results were confounded by the poor outcome of the IRS group IV patients; that is, 12 (80%) of 15 patients who did not receive local radiotherapy. However, local recurrence rates were statistically significantly lower in the IRS group III patients treated with local radiotherapy. There was little or no evidence that local radiotherapy was associated with better local control in IRS group I and II patients by univariate and multivariable analyses. This lack of evidence could be the result of the small number of local recurrences or the misclassification of patients by the IRS group classification; a total of 10 patients who were classified as IRS group I later developed local recurrence. Fontanesi et al21 noted a meaningful benefit from adjuvant radiotherapy in IRS group II and III patients in a small series of children with SS and questioned the role of irradiation in IRS group I patients. However, Blakely et al22 observed that radiotherapy decreased local recurrence rates in IRS Group I patients with high-grade nonrhabdomyosarcoma soft-tissue sarcomas and margins of normal tissue measuring less than 1 cm. Further multicenter randomized trials are needed to determine the importance of local radiotherapy in preventing local recurrence in IRS Group I patients with SS. In adult patients, local control of high-grade sarcomas has improved with radiotherapy, but this did not translate into a survival advantage with a high rate of occurrence of distant metastasis.17,23,24 The role of adjuvant chemotherapy in adults and children with SS has been controversial. Although ORs have been reported with combinations of alkylating agents and anthracycline, the influence on survival remains debatable, especially in patients with grossly resected localized tumors.15,17,19,25,26 In their individually published report, the CWS group concluded that there was a beneficial effect on outcome in their patients who received chemotherapy (compared to historical controls).5 Relative to adult patients, children and adolescents with SS have been reported to have a better outcome.16,17,19,20 Distant recurrence rates of near 40% are much higher in the adult patients compared to 21% observed in our study. Possible explanations for this discrepancy might include more widespread use of chemotherapy in the pediatric population, larger tumor sizes in the adult patients, and unknown biologic differences between the two age groups. In our study, patients who were not treated with chemotherapy had similar outcomes to patients treated with chemotherapy whether IRS Group IV patients were included in the analyses or not. The outcome for patients who had metastatic disease at diagnosis or who developed it during the course of their disease was poor despite multiple chemotherapy regimens. In contrast, in our IRS Group III patients, the observation of any response after chemotherapy was associated with better outcome. It was impossible to determine whether this finding was only associated with chemotherapy because the majority of the patients were also treated with radiotherapy and secondary surgery. Such an association may reflect the fact that patients whose tumors decrease in size after chemotherapy will have a better chance of a successful complete resection with clear margins. Furthermore, such patients may also have minimal microscopic disease, which allows the radiation oncologist to use smaller treatment fields. Our data indicate that in IRS Group III patients, chemotherapy should be used with an expected benefit of a response to facilitate secondary surgery and adjuvant radiotherapy. In agreement with several retrospective adult series of patients with SS,17,19,20 the outcomes in our study were similar in patients with IRS Group I and II disease, regardless of treatment with chemotherapy. However, given the nonrandomized, retrospective, multicenter patient-series design in our study, no conclusion can be reached regarding the effectiveness of currently used chemotherapy regimens. Nevertheless, the strong association of T1B and T2B disease with occurrence of distant metastasis warrants developing effective systemic treatment for this subgroup of patients. Thus, prospective randomized clinical trials are needed to assess the utility of chemotherapy in this disease. In our multivariable analyses, the presence of a nonextremity primary site tumor was associated statistically significantly with poor EFS and occurrence of distant recurrence. The number of patients with head and neck (n = 6) and abdomen (n = 15) tumors as primary sites was small, and the difficulty of achieving complete resection with clear margins at such locations is a likely explanation for this observation. Other investigators have also noticed a worse outcome for primary tumors in these locations.27 In our EFS analysis, biphasic histology was associated with better outcome compared with monophasic histology. The literature on adults with SS is inconsistent regarding this finding.17,20,28,29 However, in recent reports, biphasic histology was related to the presence of the SYT-SSX1 fusion transcript, which itself is associated with poor prognosis.18,28 In a multivariable analysis with 12 independent variables, it is possible to find statistically significant associations by chance alone. Therefore, we caution readers to consider our findings by evaluating the HRs and 95% CIs, by reading previously published information, and by the repetition of the significance of the variables in other analyses, instead of focusing only on the P values.
Our study has the advantage of combining four series of patients into the largest patient population of children and adolescents with SS published to date. However, institutional differences among the four participating groups in regard to procedures for diagnosis, choice of treatment, and surveillance may have influenced our analyses. As seen in Table 1
In conclusion, we have shown in a large multicenter series of SS patients, large tumor size (
We thank Gayle Nesom from the Department of Scientific Publications, The M. D. Anderson Cancer Center, Houston, TX, for help in editing the manuscript.
A.P. is currently at the Hospital for Sick Children, Toronto, ON, Canada, and A.O. is currently at Istanbul University Cerrahpasa Medical School, Istanbul, Turkey. M.F.O. is the Scott Carter Fellow of the National Childhood Cancer Foundation.
For Tables 2 Presented in part at the Thirty-Eighth Annual Meeting of the American Society of Clinical Oncology, May 18–21, 2002, Orlando, FL.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test or Fisher’s exact test was used to compare proportions. Time to local recurrence and time to distant recurrence were analyzed in the same manner as OS and EFS; however, only patients in IRS groups I to III were included in these analyses. Time to local recurrence was defined as the time interval from diagnosis to local recurrence. Patients were censored at the time of death, distant recurrence, or last follow-up evaluation if they did not have a local recurrence. Similarly, time to distant recurrence was defined as the time interval from diagnosis to distant recurrence. Patients were censored at the time of death, local recurrence, or last follow-up evaluation if they did not have a distant recurrence. 
