Introduction: Relapsed Ewing's sarcoma (ES) is an aggressive malignancy with poor survival. Conventional dose salvage chemotherapy (CC) regimens given at the time of relapse led to response rate up to 28-68% with reported event free survival (EFS) of 29% at 2 years and Overall survival (OS) of 49 % at 1 year and 28-31 % at 2 years (Van Winkle, P. et al. 2005, Magnan et al. 2015). High dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) given as induction or as part of consolidation treatment after few cycles of CC has shown benefit in improving OS and EFS in single center studies. (McTiernan et al. 2006, Barker et al. 2005) Despite report of its utility, HDCT is not generally used in United states for relapsed ES and a comprehensive search and systemic review was performed to evaluate the benefits of HDCT for this disease.
Methods: Comprehensive literature search was conducted in Medline (PubMed and Ovid SP), Embase and Cochrane Database of Systematic Review (CDSR). These databases were searched from the inception of databases till present. In addition, we manually selected more studies from bibliography data. We included studies that had relapsed Ewing's sarcoma patients and those which had mixed data for relapsed as well as primary metastatic disease treated with HDCT.
Results: Through literature and bibliography search, 1005 studies were identified and after screening, 24 studies containing a total of 1459 patients were included in the final analysis. Seventeen studies had patients with primary metastatic disease and relapsed Ewing's sarcoma. Seven had only relapsed ES patients. In the studies with relapsed patients (n = 809), EFS for most studies at two and five years ranged from 42-44% and 24-43% respectively. The OS at two years and three to five years ranged from 50-66% and 21-50% respectively. In studies with combined primary metastatic and relapsed patients (n=650), EFS at one to two years and three to five years was 45-60% and 17-47% respectively. The OS at one to two years and three to five years was 40-70% and 31-50% respectively.
Five studies (n=709) (Table 1) compared results of patients who received HDCT along with ASCT after CC to those who received only CC. Two to three and four to five years EFS for patients who received HDCT was 39-44% and 17-61% respectively, whereas it was 10-32% and 2-7% for patients who received only conventional dose therapy. OS of patients who received HDCT was 50-66% at two to three years and 42-77% at four to five years, whereas it was 14-34% and 7-10% respectively for patients who received only CC. Patients selected to receive HDCT in most of these studies were those who showed a response to initial CC (chemosensitive), either complete or partial response (CR/PR) (Rasper et al. 2014, Dirkson et al. 2014, Barker et al. 2005, Al faris et al. 2007, Frolich et al. 1999).Relapsed patients in Pole et al. (1984) survived only for three to six months. They had metastatic disease at relapse and did not receive conventional therapy prior to HDCT, possibly contributing to their decreased survival. Shankar et al 2003 reported EFS and OS at three and half years to be 14% and 28% respectively in spite of receiving CC followed by HDCT and ASCT.
Conclusions: Most studies showed that HDCT followed by ASCT given as consolidation regimen improved OS and EFS compared to CC. Two studies (Pole et al. 1984 and Shankar et al. 2003) showed lower survival after HDCT when compared to CC. Patients in Pole et al study had metastatic disease at relapse and also did not receive CC prior to HDCT, which may have affected the survival. The reason for decreased survival in Shankar et al study is not clear. Five studies which compared patients who received HDCT and ASCT in addition to CC with patients who received only CC showed improved survival in patients who received HDCT followed by ASCT. Patients selected to receive HDCT showed initial chemosensitivity (by achieving CR or PR) to CC, suggesting that proof of chemosensitive disease is an important prognostic factor for improving survival with HDCT. The heterogeneity in the data prevented us from conducting a meta-analysis. Large scale randomized control studies are needed to determine true clinical benefit of HDCT followed by ASCT in patients with relapsed Ewing's sarcoma.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.