Abstract
Aim: The aim of the present study was to evaluate the results of treatment and prognostic factors in adult patients with recurrent or refractory Ewing's sarcoma family tumors (ESFT). Patients and Methods: We retrospectively evaluated treatment outcomes of 54 consecutive patients with ESFT (aged 15 years or more) with complete medical records, who were treated with multimodal therapies after recurrence at the Istanbul University, Institute of Oncology. Results: The commonly used chemotherapy regimens at relapse were ifosfamide and etoposide (IE), ifosfamide and etoposide plus carboplatin (ICE), and oral etoposide. The median progression-free survival and overall survival for the entire group were 6.3 (95% confidence interval, 3.08-9.60) and 8.6 (95% confidence interval CI, 4.7-12.4) months, respectively. Multivariate analysis using a Cox proportional hazards model showed that non-IE/ICE chemotherapy regimens (p=0.003, hazard ratio=2.38) and the presence extrapulmonary metastases (p=0.045, hazard ratio=2.15) were associated with worse overall survival. Conclusion: In primary refractory or relapsed ESFT, the presence of extrapulmonary metastases and treatment with salvage regimens other than ifosfamide and etoposide and/or carboplatin correlate with a poor prognosis.
The Ewing's sarcoma family of tumors (ESFT) are highly malignant and very rare small round cell tumors arising from the bone and extraskeletal soft tissue. ESFT includes classic Ewing's bone sarcoma, extraskeletal Ewing's sarcoma, Askin's tumours of the chest wall, and primitive neuroectodermal tumours of bone or soft tissues.
The use of multimodal approaches that combine effective multi-agent chemotherapy with contemporary imaging, radiotherapy, and surgical techniques has dramatically improved prognosis in patients with non-metastatic ESFT at presentation over the last 30 years. While the 5-year survival rate for these patients in the 1970s was only 10%, it is now 55-75% (1-4). However, despite these improvements, the recurrence rate in patients with ESFT remains high. Approximately 30-40% of patients with a localised primary tumour and 60-80% of patients with primary disseminated disease experience a relapse (4-7). Furthermore, there has been little improvement in the survival rate of patients with metastatic or recurrent ESFT. Despite the use of conventional chemotherapy, patients with recurrent/progressive ESFT have poor prognosis, with less than a 20% chance for long-term survival (4, 5, 8-12). The successful management of patients with recurrent or refractory disease remains a largely unsolved problem; there is no standard salvage chemotherapy (13).
The present study addressed the prognostic and treatment results in patients with recurrent or refractory ESFT in addition to the prognostic variables specifically associated with improved survival.
Materials and Methods
All adult ESFT patients (age 15 years or more) with recurrent or primary refractory disease treated at the Istanbul University Oncology Institute with salvage regimens from April 1997 to December 2010 were reviewed following the acquisition of Institutional Review Board approval. A total of 98 patients were analyzed. The rate of recurrent or refractory disease was 56.1% (54/98). Patients with incomplete records or missing data were excluded. Patient characteristics are shown in Table I. All patients had initial biopsy-confirmed ESFT, as evaluated by experienced sarcoma pathologists.
The treatment decision for each patient was made by a multidisciplinary team including medical, surgical and radiation oncology specialists. All patients received multi-agent chemotherapy or standard therapy in the context of cooperative group trials as a first-line treatment. The most common initial chemotherapies included vincristine, doxorubicin, and cyclofosfamide (VDC) alternated with ifosfamide and etoposide (IE) (1), VDC with dactinomycin (1, 3), and VDC alone. In addition to chemotherapy, all patients received local treatments consisting of complete surgical excision alone, surgical excision followed by radiotherapy, or full-dose radiotherapy alone.
Recurrence was diagnosed based on physical examination, imaging, and pathology, if required. Therapy after disease recurrence was variable but usually included multimodal treatment with chemotherapy, surgery, and radiotherapy.
The most commonly used chemotherapy regimens at relapse were IE (14), IE-plus-carboplatin (ICE), oral etoposide, gemcitabine plus docetaxel, and high-dose ifosfamide (15). Chemotherapy was discontinued if the disease was unresponsive or if there was clinical or radiological evidence of progression. Surgical treatment of relapse included either primary excision/amputation or delayed resection of local or metastatic tissues. A retrospective medical chart and database review was performed to identify patient and disease characteristics at the time of diagnosis of ESFT and at the time of recurrence, the treatment received, and the outcome after recurrence. The Institutional Review Board approved the retrospective chart review for this analysis.
Evaluation and response criteria. All patients underwent re-staging at the start of treatment, with computed tomography (CT) of the chest, chest X-ray, technetium-99 bone scan, and standard radiographs and/or magnetic resonance imaging (MRI) where applicable for local recurrence. Response assessments, involving clinical assessment and appropriate imaging studies, were performed when patients exhibited no overt progression after 3 treatment cycles. Complete response (CR) was defined as the complete resolution of all objective evidence of disease for at least four weeks following treatment. Partial response (PR) required a 50% or greater reduction in the sum of the areas of all measured lesions, no increase in the size of any previous lesions, and no new lesions. Progressive disease (PD) was defined as a 25% or more increase in the sum of the areas of all measurable lesions or the appearance of a new lesion.
Statistical analysis. Quantitative data are presented as means, medians, minimums, and maximums, whereas the results of qualitative analyses are presented as frequencies and percentages. Time-to-event analyses were performed using the Kaplan–Meier method. The initial relapse-free interval (RFI) was defined as the time from initial diagnosis to first progression. Progression-free survival (PFS) was defined as the time from relapse to disease progression, death from any cause, or date of last contact. Overall survival (OS) was defined as the time from relapse to death from any cause. Differences in PFS and OS among groups were analysed using the log-rank test. Potential prognostic parameters suitable for the PFS- and OS-related data were evaluated by univariate analysis. Multivariate analysis of relative risks and 95% confidence intervals (CIs) were determined using the Cox proportional hazards model. All p-values represent two-sided tests of statistical significance. p-Values of less than 0.05 were considered statistically significant. SPSS version 16.0 (SPSS Inc., Chicago, IL) was used for the statistical analyses.
Patients' characteristics at initial diagnosis and treatment.
Results
The clinical characteristics of 54 patients (42.6% female, 57.4% male) with ESFT at initial diagnosis are listed in Table I; 34 (63%) had localised disease and 20 (37%) had evidence of disseminated disease. The median age at diagnosis was 22.0 (range: 16-39) years, and the median size of the primary tumor was 11 (range=4-21) cm. The most common primary tumor sites were the pelvis (35%) and femur (11%). All patients received chemotherapy, 47 patients (86.9%) were given radiotherapy, and 28 patients (51.8%) underwent surgery. The median follow-up period was 18 (mean=27; range=5-119) months. During this period, 40 patients (74.1%) died due to progression of the underlying malignancy and 14 patients (25.9%) remained alive with disease.
Patients' characteristics at recurrence.
Time and type of recurrence. The clinical features of patients at initial recurrence are listed in Table II. The median initial RFI was 12 months for the entire group. Patients with disseminated disease experienced relapse earlier (median time to relapse=9.4, 95% CI=6.46-12.52 months) than patients with localised disease (median= 15.8, 95% CI=10.88-20.72 months; p=0.004). The most common sites of recurrence were the lung (n=35; 63.6%) and bone (n=31; 56.3%). Relapse occurred within the first 24 months in 39 patients (72.2%) and after 24 months in 15 patients (27.8%).
Treatment after relapse. Treatment after relapse was not homogeneous, varying according to the type of relapse (systemic, local, or combined), the site of distant relapse (lung, bone, lung and bone, or other sites), the number of pulmonary metastases, and the types of first-line local and systemic treatments. Most patients received either chemotherapy alone or chemotherapy with surgery with/without radiation therapy. The most common chemotherapeutic regimens were ICE in 13 (24.1%) and IE in (20.4%); other types included oral etoposide in 14 (25.9%), docetaxel-plus-gemcitabine in two (3.7%), high dose ifosfamide in three (5.5%), and VDC in three (5.5%). Details of the chemotherapeutic agents used for the relapse treatment of these patients are mentioned in Table III. Patients who did not receive chemotherapy (n=8, 14.8%) were treated with radiation therapy (n=2, 3.7%) or palliative care-alone (n=6, 11.1%).
Chemotherapeutic agents administered for relapse treatment.
Results of salvage treatment. CR and PR were achieved in two and 13 patients, respectively, for an overall response rate of 32.6%. Patients with CR/PR received a median of six cycles (range=3-9 cycles). Seven patients (15.2%) achieved SD, and tumor progression was noted in 24 patients (52.2%).
Final outcome after relapse. The median PFS for the entire group was 6.3 (95% CI=3.08-9.60) months. The median OS was 8.6 (95% CI=4.7-12.4) months for the entire group of patients with relapse, 36.5 (95% CI=0.0-82.6) months for responders (CR/PR), and 17.3 (95% CI=0.0-39.2) months for patients with SD. The median OS was 6 (95% CI=2.6-9.4) months in patients receiving non-ICE/IE, 3 (95% CI=2.2-3.8) months in patients who did not receive chemotherapy, and 17.2 (95% CI=6.0-28.5) months in patients receiving ICE/IE-based chemotherapy (p=0.004). The cumulative 1-year PFS and OS were 20.0±9% and 36.7±7%, respectively. The estimated OS rate at one year was 63% for responders and 42.9% for patients with SD.
Prognostic factors associated with PFS and OS. Based on univariate analysis, the location of the primary tumour in the central axis was associated with short post-recurrence PFS (Table IV). A central location of the primary tumor, presence of extrapulmonary or brain metastases, and the use of chemotherapy other than ICE or IE as salvage treatment during relapse were associated with poor survival post-recurrence. Relapse within 24 months, the presence of bone metastases, and receiving fewer than eight cycles of chemotherapy at the start of therapy had borderline significance (Table V). The prognostic variables for OS with significance in univariate analysis were included in the multivariate analyses using a Cox proportional hazards model, which showed that the use of non-IE/ICE chemotherapy regimens (p=0.003, hazard ratio=2.38) and extrapulmonary metastases (p=0.045, hazard ratio=2.15) were associated with poorer OS.
Univariate analysis of factors predictive of post-recurrence PFS.
Discussion
Superior multimodal therapeutic regimens combining more intensive systemic treatment with chemotherapy, better surgical approaches, and advanced radiotherapy planning have reduced the frequency of ESFT recurrence (16). Nevertheless, 30-40% of patients still experience recurrence, whether local, distant, or both. The recurrence of ESFT is most common within two years of initial diagnosis (17), which is similar to our findings. The treatment of this group of patients remains unsatisfactory and controversial, and few reports have addressed their management.
Univariate analysis of factors predictive of post-recurrence survival.
Various chemotherapeutic and biological agents have been investigated to identify combinations that possess significant anti-tumour effects against refractory ESFT. The combination of topoisomerase I or II inhibitors with alkylating agents and several myeloablative high-dose consolidation therapy regimens are currently used to treat recurrent ESFT and can be considered when treating these patients (13, 14, 18-21). The ifosfamide–IE combination failed to significantly increase long-term survival in recurrent ES, despite achieving response rates of 21-50% (14, 22). Topotecan plus cyclofosfamide produced responses in approximately 35% of patients with recurrent ES (23, 24). A study at our Institute showed that a modified combination of vincristine, topotecan, and cyclofosfamide was effective and tolerable; an objective response rate of 50% was attained in children and adolescents with recurrent/progressive ES (25). The combination ICE regimens demonstrate a response rate of up to 48% but cause substantial haematological toxicity (26, 27). A summary of 71 ESFT cases at St. Jude Children's Research Hospital from 1979 to 1999 also showed poor 5-year OS (17.7%) and improved OS associated with RFI ≥24 months (11). The most common second-line chemotherapy was ICE. There was no significant difference in 5-year OS between patients treated with ICE (24%) and those treated with other chemotherapy regimens (16%). Treatments other than ICE or IE were associated with short survival in the current study. Beyond demonstrating the efficacy of ICE or IE treatment, this result reflects that the patients undergoing such aggressive treatment have better performance status and are thus more suitable for curative and definitive treatments. In our experience, patients who received ICE or IE also underwent surgical and other curative treatments, while patients who received other treatments, such as oral etoposide, mostly received palliative and symptomatic treatment.
A phase II study of high-dose ifosfamide for recurrent ES demonstrated a 34% overall response rate but resulted in significant haematologic and CNS toxicity (20). Retrospective studies reported an overall objective response rate of 63% and a CR rate of 26% (5/19 patients) for protracted irinotecan in combination with temozolomide for recurrent/progressive ES (26, 27). Several studies combining stem cell transplantations with other chemotherapies and radiation therapies achieved encouraging or mixed results (16, 28-31). Other aggressive attempts to control the disease, including myeloablative regimens, have been used, but there is currently no evidence that myeloablative therapy is superior to standard chemotherapy (32).
Because the EWS-ETS fusion protein is unique to ES and is present in almost all cases, this protein or the critical gene products regulated by the fusion protein are ideal tumour-specific targets. The expression of EWS-FLI1 likely represents the decisive transformational event activating the pro-survival, pro-proliferation, and pro-metastatic pathways that result in clinically apparent ES. The characterisation of these pathways will identify new therapeutic targets, which may be particularly useful in patients with ES with metastatic and/or recurrent disease. Studies with monoclonal antibodies against insulin-like growth factor receptor have shown preliminary potential but have yet to demonstrate meaningful improvement. Although producing objective responses, including prolonged time-to-progression compared with historical controls, in approximately 10% of patients with metastatic recurrent ES (33, 34).
Although our center is a tertiary cancer Center where combined multimodal therapy is used efficiently by specialists who are experienced in the treatment of sarcoma, the time to relapse and the survival time in our study were relatively shorter compared with previously published studies (10, 12). This finding may be due to axial involvement as the most common primary site in this study; therefore, radical radiotherapy has been often used instead of curative surgery in such patients with unresectable disease. The inclusion of a considerable number of patients with early relapse, as well as those with primary refractory diseases may have led to worse outcomes in our patient cohort.
In primary refractory or relapsed ESFT, patients with extrapulmonary disease were associated with worse OS in our study. Several studies have reported improved survival in patients with lung-only systemic relapses versus those with other combinations of distant recurrence (12, 35, 36). In the report by Bacci et al. (35), 48% of patients who had lung-only metastases achieved remission after relapse, in contrast to 2.4% of patients with bone recurrences, and 0% of patients with other combinations of distant relapses.
Over the past several decades, through multidisciplinary approaches and cooperative trials, there have been great improvements in the outcomes of patients with ESFT. However, even with improved primary treatment for ESFT, recurrent disease remains a significant clinical problem for medical oncologists. Our retrospective analysis confirms the poor overall outcome after relapse of ESFT reported by others. Tumour response to chemotherapy may affect OS. Because the presence of pulmonary metastasis-alone is correlated with a good prognosis in patients who experience a disease relapse, local and aggressive systemic treatments must be attempted whenever possible.
Footnotes
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Conflicts of Interest
The Authors declare that they have no conflicts of interest.
- Received November 17, 2013.
- Revision received January 24, 2014.
- Accepted January 29, 2014.
- Copyright © 2014 The Author(s). Published by the International Institute of Anticancer Research.
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