The treatment of ESFT has evolved over the last decades; systemic treatments have become more intensive, and local control measures more aggressive. As we advance toward the new generation of studies, a critical evaluation of our current understanding of the treatment of this malignancy must be performed, and the relative contribution of each of the therapeutic components should be analyzed. In this review of the experience of the St. Jude Children's Research Hospital with the treatment of ESFT over the last 20 years, we have analyzed the advances made with each consecutive study.
Advances in the Treatment of ESFT
The 5 consecutive institutional studies are representative of the advances identified internationally in the management of this neoplasm. Treatments built on the efficacy of the 4-drug regimen that was used in the ES79 protocol,6 first by adding the IE pair (the ES87 protocol),7 and then by intensifying therapy and increasing cumulative doses with the addition of granulocyte–colony-stimulating factor (G-CSF) and improvements in support measures (the EWI92, SJBCM, and HIRISA protocols).3 As systemic approaches evolved, so did local control techniques. Although nearly two-thirds of patients in the earlier studies received definitive RT for local control, the majority of patients currently are treated with either surgery or a combination of surgery and RT.
The ES79 protocol was a variant of the 4-drug VACD regimens that were used by American and European cooperative groups.11–16 Similar to the ES79 protocol, surgery was seldom used, and RT alone was used in >75% of the patients.11, 12, 15, 17–19 The ES87 protocol built on the evidence indicating the efficacy of IE,20 and incorporated this pair into a VACD backbone.7 However, using similar local control approaches to the ES79 protocol, the addition of IE in the ES87 protocol did not appear to improve the outcomes. Contemporary to the ES87 protocol were 2 multi-institutional randomized studies that investigated the impact of adding etoposide to the VACD and the VAID (in which ifosfamide replaced cyclophosphamide) regimens.4, 21 In the POG8850/CCG7881 trial, all patients were randomized to receive VACD with or without IE.21 Among patients with metastatic disease, the addition of IE did not prove to be advantageous. However, for patients with nonmetastatic disease, the VACD/IE regimen was found to be superior to the standard VACD regimen (5-year EFS of 69% ± 3% vs 54% ± 4% respectively [P = .005]).21 The ES87 protocol demonstrated slightly inferior results for patients with localized disease compared with the experimental arm of the cooperative study (5-year EFS rate of 58.1% ± 8.6% vs 69% ± 3%, respectively), but likewise, the outcome for patients with localized disease on the ES79 protocol was superior to that reported on the standard treatment arm of the cooperative group study (5-year EFS rate of 60.7% ± 6.2% vs 54 % ± 4%, respectively).
ESFT are very sensitive to alkylating agents, which have a very steep dose-response curve, and the next generation of studies aimed at increasing the total cumulative doses of the active agents, as well as intensifying therapy by increasing the number of doses per cycle and per unit of time, with G-CSF support (Table 1). This approach was evaluated by the EWI92 protocol.3 The results of this study were superior to the prior 2 regimens; however, only 66% of patients completed therapy.3 The importance of dose intensification was also evaluated in the POG9354/CCG7942 trial, in which patients were randomized to receive alternating courses of VCD and IE over either 48 weeks or 30 weeks. The early results of this trial demonstrated no significant difference in outcome between the standard and the dose-intensified arms (3-year EFS of 76% ± 4% vs 74% ± 4%, respectively [P = .57]).5
An analysis of the contributions of each of these consecutive studies appears to demonstrate that improvements were obtained over the years. Although the addition of IE in the ES87 protocol did not add a significant survival advantage to the ES79 VACD regimen, the results of the subsequent studies that explored more intensive therapy would suggest that more aggressive regimens result in better disease control. When the 3 intensive protocols (EWI92, HIRISA, and SJBCM) were compared with the first studies (ES79 and ES87), a trend toward improved survival was found for those patients with localized disease who were treated with the more intensive regimens (5-year OS of 83.1% ± 5.6% vs 68.5% ± 4.8% [P = .068]). However, these improvements must be interpreted in the context of more aggressive and evolving surgical and RT techniques, which resulted in improved local control in the later studies.
In this context of escalating intensity and improved local control, the results of the ES79 protocol compare very favorably with the studies that followed. The ES79 protocol was a simple, relatively nontoxic regimen that used fractionated cyclophosphamide over 7 days, instead of the single high dose that became the norm afterward. A major positive impact has been attributed to the introduction of ifosfamide in current regimens, but accurate comparisons between the antitumor effect of ifosfamide and cyclophosphamide are limited by the differences in their administration. Ifosfamide has been typically administered in fractionated doses because autoinduction of enzyme activity increases the concentration of the active metabolites of alkylating agents. This effect has been demonstrated for both cyclophosphamide22, 23 and ifosfamide.24–26 Single-dose administration of these alkylating agents may result in decreased bioactivation because of saturable kinetic mechanisms, which favor the inactivating elimination pathway.27, 28 Therefore, fractionated administration alters kinetic properties avoiding the elimination pathways and favoring bioactivation of enzyme activity; however, this advantageous phenomenon has been applied to the administration of ifosfamide only, whereas cyclophosphamide continues to be administered as a single dose in the majority of ESFT protocols. Given this pharmacokinetic rationale and the results of the ES79 protocol, we may wonder whether the potential of the VACD regimen has been reached.
As expected, older age, pelvic primary tumor, large tumors, and metastatic disease were associated with worse outcome,21, 29, 30 but only stage of disease and tumor size retained significance on a multivariate analysis. The relative importance of some of these factors has diminished with better systemic and local control. The most important prognostic factors for patients with localized disease was the local and systemic treatment. Local control with both surgery and RT was found to result in the best outcome, as did more intensive systemic therapy. However, because local and systemic therapy evolved simultaneously, it is difficult to determine the relative benefit of each advance. For patients with metastatic disease, the only prognostic indicator was the pattern of metastasis. Our analysis confirms that patients with pulmonary and extrapulmonary metastases differ with regard to the probability of survival.31, 32
Older age is consistently associated with a worse outcome.21, 29, 30, 33 Survival appears to decrease steadily with increasing age. Furthermore, patients aged >14 years are reported to have a higher proportion of large tumors and pelvic primary tumor sites29 as well as of metastatic disease.33
The cumulative incidence of second neoplasms in the majority of series published to date is no higher than 2%,21, 34 and sarcomas arising in the radiation field represent >75% of the cases.35, 36 However, in the current series, hematologic malignancies accounted for approximately two-thirds of second neoplasms. Current protocols that include intensification of alkylators and topoisomerase-II inhibitors have resulted in a significant increase in the incidence of t-AML/MDS.33, 37–39
Risk Stratification in ESFT
The advances of the last 20 years represented in the current series have defined the basic guidelines for the multidisciplinary treatment of patients with ESFT, including better characterization of the active drugs and local control measures. The majority of current protocols have focused on chemotherapy intensification. However, it is possible that subgroups exist in which a less intensive regimen may be used. Modern regimens should take into consideration risk factors that will help in adapting the intensity of the therapy. Although we acknowledge the limitations of exploratory analyses, the results of the current study demonstrated that patients can be risk stratified on the basis of simple clinical factors; these models can be refined further by incorporating additional variables, such as histologic response to chemotherapy30, 40 or the molecular detection of circulating tumor cells or bone marrow micrometastases.41 With a better understanding of the biology of ESFT, molecular markers may help improve these risk stratification approaches.