At present, no standard treatment model has established for adult ES and the management is often institution-specific [19–22]. Even for the most commonly used VDC/IE chemotherapy regimen, the number of cycles ranges from 6 to 17 in different studies [23, 22, 5]. The optimal chemotherapy regimen for adult ES is controversial . Tao et al. reported that there were no significant differences between anthracycline and platinum based chemotherapy regarding EFS and OS . In contrast, Casey et al. and Ahmed et al. reported that treatment according to the pediatric protocol was significantly associated with improved survival [24, 21]. In the present cohort, we also followed the pediatric VDC/IE protocol, unfortunately 50 patients didn’t completed the planned 17 chemotherapy cycles due to various reasons: the most common reason was lack of money (21 patients, 42%), followed by the belief that adults inevitably fare worse than children and increasing chemotherapy duration may not lead to improvement in survival (16 patients, 32%), toxicity-related treatment abandonment occurred in eight patients (16%), and other reasons accounted for five patients (10%). Overall, VDC/IE chemotherapy was well tolerated in our patients. Our study provided real-world data in adult ES from Asian developing countries, and the aforementioned situation provided an opportunity for comparative analysis between different chemotherapy cycles and intervals.
It was reported that adult patients with ES had a worse prognosis compared to pediatric patients [5, 9, 23, 25–27]. As far as nonmetastatic ES was concerned, Granowetter et al. reported that the 5-year EFS was 77.5% for patients age 1 to 9 years, 69.4% for patients age 10 to 17 years, and 63.2% for patients older than 18 years . Womer et al. reported that the 5-year EFS was 72% and 47% for patients younger and older than 18 years, respectively . In the present study, we also observed a poor prognosis for adult ES, with a 5-year OS of 33.0% and EFS of only 22.0%. The reasons behind the poor prognosis for adult ES are unclear. Generally, the prognostic factors of ES include site of primary disease, tumor volume, response to chemotherapy, and presence of metastatic disease at diagnosis [28, 12, 13]. It is not clear if these findings from pediatric studies also apply to adults because several case series suggested that ES in adult populations was a more biologically aggressive variant of the disease [27, 3]. However, there is a uniform consensus that patients presenting with metastatic disease have an extremely poor prognosis, regardless of age. In our cohort, 40.7% of patients presented with metastatic disease at diagnosis, slightly more compared with other series [24, 29, 30], this may partially justify the dismal survival. When patients with metastatic disease at presentation were excluded, the 5-year OS and EFS increased to 44.0% and 31% for the remaining 48 patients in the present study. Notsurprisingly, this outcome was worse than that of aforementioned pediatric patients with localized ES [5, 9]. However, these figures were still fewer than those from other recent adult cohorts: OS of 66% and EFS of 44.0 % in the Casey et al. series of 76 cases , OS of 66% and EFS of 43.0 % in the Fizazi et al. series of 129 cases .
To identify the factors that potentially affect the outcomes of our cohort, we conducted exploratory univariable and multivariable analyses. Interestingly, besides metastatic disease at diagnosis, chemotherapy of less than 12 cycles was also detrimental to both OS and EFS of our patients. Moreover, a high frequency of chemotherapy delays (≥ 25%) was an unfavorable independent predictor of OS. As mentioned above, the number of chemotherapy cycles positively correlated with the chemotherapy doses and the frequencies of chemotherapy delays positively correlated with chemotherapy intervals. These findings suggested that the poor prognosis in the present study was partially due to insufficient chemotherapy doses and prolonged dose intervals. Dose-dense chemotherapy with shortening intervals showed an increase in survival of ES , whereas the benefit of dose escalation (increasing the dose of chemotherapy agents) studies has been less consistent and may be accompanied by other dose-limiting toxicities . It was reported that lower doses of alkylating agents were detrimental to survival of ES , however, dose escalation of alkylating agents in the VDC/IE regimen did not improve the outcome for patients with localized disease . Based on our results, we strongly recommend aggressive treatment for adult ES to maintain adequate chemotherapy doses and appropriate intervals, with the help of supportive treatment. None of the other factors such as extremity/axial primary site, skeletal/extraskeletal tumor origin, diameter of primary tumor, local therapy modality and time to local therapy achieved statistical significance, but age older than 30 years at diagnosis (HR 1.45, P = 0.183) showed a trend toward significance for OS. Although chemotherapy cycles and intervals can be affected by chemotherapy toxicity, the univariable analysis indicated that grade 3–4 chemotherapy toxicity didn’t affect the EFS and OS of our patients significantly.
To further explore the potential racial disparity in survival of adult ES, we reviewed the outcomes of localized disease treated with similar cycles of VDC/IE regimen (Table 5). The prognosis of our patients was better than that of Canadian series, while it was a little worse than the prognosis of cohorts from the USA and Turkey. The results showed no evidence of ethnical disparity in survival of adult ES. Further head-to-head comparative studies are needed to clarify this question.
Patients who receive high doses of anthracyclines are at risk for cardiotoxicity, dexrazoxane is often used as a cardioprotectant when prior doxorubicin reached a cumulative dose of 300 mg/m2 . But controversy exists if dexrazoxane reduces the antitumor effect of doxorubicin and increases the risk of second primary malignancies . In the present study, we found that there were no differences of EFS and OS in patients with or without administration of dexrazoxane (log-rank test, P > 0.05), and there was no second primary malignancy occurred during the follow-up period. Our results were consistent with the findings from other recent large population-based studies [34, 35, 32].
This study has several limitations. First, it was a retrospective, single-institution study with a small sample size. As a consequence, it was difficult to draw conclusions on all factors influencing outcomes. Second, we excluded patients for whom there was incomplete clinical data or evidence of disease progression before completing first-line therapy. This could have resulted in selection bias. To assess accurately the outcomes and prognostic factors of adult ES, large prospective clinical trials are needed.