Prognostic factors in advanced synovial sarcoma: an analysis of 104 patients treated at the Royal Marsden Hospital

E. L. Spurrell*, C. Fisher, J. M. Thomas and I. R. Judson

Sarcoma Unit, Royal Marsden Hospital, London, UK

* Correspondence to: Dr E. Spurrell, Department of Medical Oncology, King George V Building, 1st Floor, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK. Fax: +44-20-7786-9414; Email: emma.spurrell{at}icr.ac.uk


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Aims: Key prognostic factors at diagnosis of synovial sarcoma are well defined from the literature. There are few data regarding prognostic parameters in the setting of advanced disease. Our aim was to look specifically at a cohort of patients with advanced synovial sarcoma and to identify potential prognostic factors.

Patients and methods: One hundred and four patients with advanced synovial sarcoma were identified from the Royal Marsden Hospital's sarcoma database between 1978 and 2003. Patient data were analysed retrospectively. Most patients were aged between 20 and 50 years at diagnosis. Seventy-one patients were deceased at the time of analysis. Ninety-two patients received chemotherapy for management of advanced disease (most commonly doxorubicin + ifosfamide).

Results: Median survival following development of advanced disease was 22 months. Predictors of survival with advanced disease were age <35 years (P=0.03) and response to first-line chemotherapy (P=0.05). The response rate to doxorubicin plus ifosfamide was 58.6%, and this was superior to either agent when given singly. Metastasectomy was not associated with improved prognosis in this series.

Conclusions: Synovial sarcoma is a chemosensitive soft tissue sarcoma. Compared with historical controls, survival with advanced disease seems to have improved over the years, possibly as a result of better use of chemotherapy. Age <35 years and response to first-line chemotherapy predict for improved survival with advanced disease.

Key words: doxorubicin, ifosfamide, prognosis, synovial sarcoma


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Soft tissue sarcomas (STS) are rare tumours of connective tissue. They account for ~1% of all cancers worldwide each year. Synovial sarcoma represents ~5–10% of all STS [1Go]. It affects young individuals, mostly within the range of 15–40 years of age. There is a slight male predominance.

Despite its name, synovial sarcoma is not thought to derive from synovial tissue, sometimes occurring near but never within a joint, and its cellular origin is undefined [2Go]. The term synovial sarcoma stems from early literature as a result of the tumours microscopic resemblance to developing synovium. The tumours are classified into three principal histological types: biphasic, monophasic and poorly differentiated. The biphasic type consists of both spindle cell and epithelial components (containing glandular structures) in equal proportions [2Go]. The monophasic type comprises spindle cells with no, or very few, glandular epithelial cells [2Go]. The poorly differentiated type resembles the small round cells seen in Ewing's/primitive neuroectodermal tumour, but is identified as synovial sarcoma by its characteristic immunohistological, ultrastructural and cytogenetic features [2Go].

The natural course of the disease is such that many patients will experience recurrence of the primary tumour and/or metastatic disease. Metastatic disease occurs in ~50% of patients. The most common site of metastasis is the lungs, occurring in 74–81% of patients with metastatic disease [3Go, 4Go], lymph node metastases, occurring in 3–23% [3Go–5Go], and bone metastases, occurring in 10–20% [3Go, 4Go].

It is well known from the literature that the key prognostic factors at diagnosis of synovial sarcoma are tumour size [5Go–16Go], grade [9Go–11Go, 15Go–18Go], age of patient [6Go, 7Go, 13Go, 14Go, 16Go, 17Go, 19Go], clear surgical margins [6Go, 8Go–10Go, 16Go, 17Go, 20Go, 21Go] and adjuvant radiotherapy [22Go–24Go]. There are few data regarding prognostic parameters in the setting of advanced disease. Our aim was to look specifically at a cohort of patients with advanced synovial sarcoma and to identify prognostic factors important in this setting. We were also interested in the response rates achieved with first-line chemotherapy in synovial sarcoma and whether or not chemotherapy in advanced disease affects survival (although in the absence of a randomised controlled trial we recognise that this is speculative).


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Prior to the study, local research ethics committee approval was obtained.

The Royal Marsden Hospital's prospectively gathered sarcoma database was used to identify patients treated for advanced synovial sarcoma. The patient population included patients registered between March 1978 and February 2003. Data regarding each patient were gathered from patients' clinical notes, the Royal Marsden Hospital's electronic patient record and the patient's general practitioner where necessary.

In all cases histology was reviewed by a specialist soft tissue pathologist on referral to the Royal Marsden Hospital. Date of histological confirmation of diagnosis was recorded. Data gathered at diagnosis included histological subtype, site of primary tumour, stage of primary tumour and management of primary tumour (surgery, adjuvant/neo-adjuvant radiotherapy, adjuvant/neo-adjuvant chemotherapy). At the point of advanced disease, the information gathered included date and site of metastases or local recurrence (LR), and chemotherapy for advanced disease including agents used, number of courses given and responses. Also recorded was whether patients received palliative radiotherapy or underwent metastasectomy. Most of the data at the point of advanced disease were gathered retrospectively. Nine patients were excluded due to insufficient data.

Definitions
Tumours were subclassified into monophasic, biphasic and poorly differentiated, and graded according to the Trojani system [25Go]. Patients were staged according to the Royal Marsden Staging System as published by Ramanathan et al. [26Go].

The outcome status of each patient was recorded as of May 2003. Patients were recorded as being either dead from disease, alive with disease or alive disease-free.

Advanced disease was defined as metastatic disease, LR not amenable to complete surgical excision or primary tumour not amenable to complete surgical excision.

Response to chemotherapy was analysed as a binary variable: responders being those reported as having achieved a complete or partial response and non-responders those reported as showing stable or progressive disease. Patients were re-imaged after every two cycles of chemotherapy as per unit policy. Response to chemotherapy was recorded via retrospective viewing of radiology reports [most reports using Response Evaluation Criteria In Sold Tumors (RECIST), but historical reports using WHO criteria].

Statistical methods
Life table curves were calculated using the Kaplan–Meier method and compared with the log-rank test; a test for trend was employed for ordered categories. Analysis of the effect of potential prognostic factors was undertaken using Cox's regression. A test for trend was used for ordered categories or continuous variables; otherwise a test for heterogeneity was employed. Tabulated data were analysed using the {chi}2-test unless one of the parameters was ordinal, in which case the Mann–Whitney test or Spearman rank correlation was employed. Fisher's exact test was used for 2 x 2 tables.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Patient characteristics
One hundred and four patients were included in the final analysis. These patients were selected for the fact that they had advanced disease, regardless of the treatment that they received in this setting. The patient population included patients who were referred to the Royal Marsden Hospital at diagnosis, as well as those referred at the point of advanced disease (the primary tumour having been managed at other centres on diagnosis). Table 1 shows a summary of the characteristics of the patients included in the analysis.


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Table 1. Patient characteristics

 
There were equal numbers of males and females, and most of the patients were aged between 20 and 50 years at diagnosis. The youngest patient was 3 years old at diagnosis and the oldest 69 years. The median age at diagnosis of advanced disease was 33 years. Most of the primary tumours were located in the lower limbs. Only 10 tumours were T4. There was an even distribution between tumour grades 2 and 3 and between monophasic and biphasic histological subtypes. Only nine of the tumours were poorly differentiated.

Management of the primary tumours was in accordance with standard care, most patients having undergone surgery as well as radiotherapy.

Of the 104 patients, 12 did not have metastatic disease. In these patients advanced disease represented advanced LR or primary tumour not amenable to surgical excision. Of the 89 patients who had metastatic disease, 69 had metastases to the lungs and 35 of these underwent metastasectomy.

Twelve patients did not undergo chemotherapy for advanced disease. Five of these patients had lung metastases treated with metastasectomy, four of whom are alive disease-free. Three patients had advanced LR, two of whom are dead from disease; one is alive with disease. One patient died of brain metastases. In three patients the reason for the decision not to give palliative chemotherapy was not given.

Outcome
Ten patients were lost to follow-up, the principal reason being that they returned to their country of origin. Seventy-two patients were recorded as deceased, all secondary to synovial sarcoma except one who died in a road traffic accident. Of the 22 patients alive as of May 2003, eight are presumed disease-free.

The median survival following a diagnosis of advanced disease was 22 months. In this cohort, 74% of the patients had developed metastatic disease by 5 years and 81% by 10 years (Figure 1). Patients within our cohort whose diagnosis of synovial sarcoma was made within the last 5 years (1998–2003) were excluded from the survival curve to avoid biasing the sample. This is because remaining patients also diagnosed within this period but who have not yet developed metastatic disease are by definition excluded; and most patients would be expected to have developed metastatic disease within 3–5 years. In those patients who developed a metastasis, median time to metastatic disease from diagnosis was 16 months (Figure 1).



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Figure 1. Kaplan–Meier curve showing the time from diagnosis to metastatic disease in patients diagnosed with synovial sarcoma between 1978 and 1998.

 
Prognostic factors
Univariate analysis of predictors of survival following diagnosis of advanced disease is shown in Table 2. Patients aged under 35 years (median age at diagnosis of advanced disease rounded up to the nearest 5 years) were more likely to survive longer with advanced disease (P=0.03). Figure 2 shows that response to first-line chemotherapy for advanced disease was predictive of survival with advanced disease (P=0.05). Figure 3 shows that if patients with stable disease (SD) in response to first-line chemotherapy are included amongst the responders, there remains a significant survival advantage (P=0.008). Five of the 92 patients who received chemotherapy are excluded from these curves because response was unknown.


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Table 2. Univariate analysis of prognostic factors in patients with advanced synovial sarcoma

 


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Figure 2. Kaplan–Meier curve comparing the survival following first-line chemotherapy for advanced disease between responders to chemotherapy and non-responders. HR, hazard ratio; CI, confidence interval.

 


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Figure 3. Kaplan–Meier curve comparing the survival following first-line chemotherapy for advanced disease between responders to chemotherapy and non-responders. Included among responders are patients with SD. PD, progressive disease; SD, stable disease; CR, complete response; PR, partial response; HR, hazard ratio; CI, confidence interval.

 
Chemotherapy
Ninety-two patients out of 104 received at least one cycle of chemotherapy for advanced disease. Forty-eight patients had second-line chemotherapy, 19 third-line, four received fourth-line and two went to seventh-line. Table 3 shows the frequency of different regimens used for first-line treatment of advanced disease in this cohort as well as the median number of cycles received by each patient. Response rates to the most commonly used regimens are shown in Table 4. The best response rate was achieved with the combination of doxorubicin and ifosfamide (58.6%). This was significantly superior when compared with ifosfamide alone [response rate (RR) 25%; P=0.025] and almost significantly superior compared with doxorubicin alone (RR 25%; P=0.06).


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Table 3. Frequency of different regimens used as first-line chemotherapy for advanced disease

 

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Table 4. Response rates to the most commonly used chemotherapy regimens and comparisons of efficacy

 
Metastasectomy
Thirty-five patients underwent metastasectomy. Twenty-five underwent the procedure once, seven twice and three patients underwent the procedure three times. Age, stage at diagnosis, tumour grade, histological subtype, gender and time to advanced disease were not associated with metastasectomy in this cohort. As a time-dependent covariate for survival, we found no evidence that patients in this cohort who underwent metastasectomy had a different prognosis from those who did not (P=0.33; hazard ratio 0.71).


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Synovial sarcomas are rare tumours, with ~200 new cases being reported each year in the UK and ~800 cases a year in the USA [2Go]. Over the last 5 years, on average 15 cases per year have been referred to the Royal Marsden Hospital. A previous report from this unit examined prognostic factors from the time of diagnosis and reported the impact of primary disease management [6Go]. In this analysis our aim was to characterise variables that may influence survival in patients with advanced disease. We did not look at the effect of these prognostic factors on overall survival due to the bias incurred by extrapolating data from a selected subgroup of patients to an overall patient population.

Since the early large analyses of synovial sarcoma in the 1960s, figures for 5- and 10-year survival have improved over time. Five-year survival has improved from reported figures of 25–51% in the 1960s [4Go, 27Go] to 63–75% reported in the last 3 years [7Go, 10Go, 12Go], and 10-year survival from 11% in 1965 [4Go] to 50% in 2000 [7Go] (Table 5).


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Table 5. Summary of the literature since the 1960s specific to synovial sarcoma

 
In our cohort the main predictors of survival with advanced synovial sarcoma were age <35 years and response to first-line chemotherapy. These parameters were independent of each other and independent of tumour grade, stage at diagnosis and the time to advanced disease (Spearman rank correlation, not significant). One interpretation of these findings is that while tumour size and grade are known to influence the risk of developing metastatic disease, and hence prognosis, these become irrelevant once metastasis has occurred. We excluded the possibility that patients aged <35 years show improved survival with advanced synovial sarcoma due to greater use of combination chemotherapy regimens compared with those those >35 years (33% and 24%, respectively; P=0.35). We have also shown that SD in response to first-line chemotherapy has a clinically important survival advantage (Figure 3). The observation that SD has the same survival advantage as response to chemotherapy in STS has been shown previously [28Go].

Median survival with advanced disease in this cohort was 22 months. Using the data in Table 5 as historical controls, there is a suggestion that length of survival with advanced disease has improved since 1970. One explanation for this may be improved diagnostic techniques since 1970 and therefore earlier detection of metastatic disease (lead time bias). However, median time to metastasis in our cohort was 16 months, a figure that has not changed significantly since 1970 according to published data (Table 5).

If improved survival with advanced synovial sarcoma is a genuine phenomenon, then the possible explanations include improved chemotherapy regimens and the use of pulmonary metastasectomy. As mentioned, in our cohort, response to first-line chemotherapy predicted for survival with advanced synovial sarcoma. Synovial sarcoma is generally regarded as a more chemosensitive STS (other than Ewing's), but this is based on trials with small numbers of patients [29Go–33Go]. The published response rates to chemotherapy in STS range from 28% to 47% [29Go, 30Go, 34Go–38Go]. A response rate of 58.6% to doxorubicin + ifosfamide in our cohort would support the argument that synovial sarcoma is a chemosensitive STS. The suggested improved survival with advanced disease in our cohort and its association with response to first-line chemotherapy is significant in view of recent retrospective data showing that disease specific survival rates have not changed for STS since 1982 [39Go]. In the analysis mentioned, synovial sarcoma represented only 14% of the cohort [39Go]. Synovial sarcoma may represent a subgroup of STS where improved survival with advanced disease can be attributed to its chemosensitivity.

Approximately half of the patients with lung metastases underwent metastasectomy. This high percentage simply reflects unit policy. Despite this, however, we did not show that metastasectomy improved survival with advanced synovial sarcoma. This is contrary to the experience of metastasectomy for STS published from Memorial Sloan Kettering Cancer Center [40Go, 41Go]. Synovial sarcoma accounted for a small percentage of the patients represented in these cohorts (14% [41Go] and 22% [40Go]). Further assessment of the role of metastasectomy specifically in synovial sarcoma is necessary to address this issue.

Despite attempts to minimise bias where possible, this analysis was performed retrospectively, making the data vulnerable to criticism. The chemotherapy data are vulnerable in two areas. First, 17 different chemotherapy regimens were used as first-line for advanced disease due to a number of patients being treated in clinical trials, as well as changes in standard management over the years. However, most patients received doxorubicin or ifosfamide alone or in combination, and most of the remaining regimens were anthracycline-containing. For these reasons we cannot make any direct comparisons in terms of response to chemotherapy with other published studies. For the purpose of making correlations between response and survival we simply divided patients into responders and non-responders.

Although these patients were an unselected case mix, there were few T4 primary tumours and most patients were Royal Marsden Hospital stage II at diagnosis. This might imply that our cohort represented a better prognosis group at diagnosis. However, our statistical analyses did not show that stage at diagnosis influenced outcome once a patient had developed advanced disease. We did not address the effect of these prognostic parameters on overall survival.

The EORTC Soft Tissue and Bone Sarcoma Group published an analysis of prognostic factors with advanced STS in 1999 that included 120 patients with synovial sarcoma [38Go]. This analysis was concerned with identifying prognostic factors important in the setting of advanced STS, particularly regarding the outcome of first-line chemotherapy. Unlike our study, these patients were enrolled prospectively into seven different chemotherapy studies, thus reducing the risk of biased methodology, although the re-analysis of these studies looking for prognostic factors was performed retrospectively. In terms of patient selection bias, those included in the EORTC analysis were selected for entry into chemotherapy trials and patients with poor performance status or significant co-morbidities would have been excluded, unlike our patient group. Our definition of advanced disease included advanced unresectable primary, advanced unresectable LR and metastatic disease, which was identical to the criteria used for the EORTC analysis. The EORTC study also found young age to be predictive of survival with advanced STS, but unlike our study, a long disease-free interval was also predictive of survival and the subgroup of patients with synovial sarcoma did not show a significantly higher response rate to chemotherapy compared with other STS (although they were at the higher end of the scale when looking at the raw data).

This analysis by our unit was prompted by debates within the literature suggesting that survival with STS has not altered significantly over the years despite improved local control techniques and aggressive management of advanced disease. We were interested in patients with advanced synovial sarcoma due to its perceived chemosensitivity. Although our analysis showed that the rate of metastasis and the metastasis-free interval have not altered significantly over the last 30 years, survival with advanced synovial sarcoma does seem to have improved over time. Young age and response to first-line chemotherapy are good prognostic indicators in advanced disease. The improved survival with advanced disease may be attributable to its chemosensitivity and improved chemotherapy regimens. It is impossible to conduct randomised controlled trials including a ‘no treatment’ arm in advanced STS. However, if combination chemotherapy is indeed superior in terms of response rate, progression-free and even overall survival, then a randomised controlled trial currently being carried out by the EORTC Bone and Soft Tissue Sarcoma Group may help to answer the question. This study compares standard dose single agent doxorubicin with a doxorubicin and ifosfamide combination, and will address specifically progression-free survival.


    Acknowledgements
 
Mr Omar Al-Muderis, data manager at the Royal Marsden Hospital Sarcoma Unit, assisted in identifying the cohort analysed. Mr Roger A'Hern assisted in the statistical analyses.

Received for publication June 29, 2004. Revision received September 30, 2004. Accepted for publication October 22, 2004.


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 Abstract
 Introduction
 Methods
 Results
 Discussion
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