high-dose chemotherapy and stem cell rescue for high-risk ewing’s family of tumors

251

Review

www.expert-reviews.com ISSN 1473-7140© 2011 Expert Reviews Ltd10.1586/ERA.10.215

The Ewing’s family of tumors (EFT) includes Ewing’s sarcoma (ES) neuro-ectodermal tumor (PNET) and Askin’s soft-tissue tumors. EFT occurs most frequently in the second decade of life and accounts for 4% of overall childhood and adolescent malignancies. EFT also com-ancies. EFT also com-prises of approximately 34% of pediatric primary malignant bone tumors [201]. Marked improve-ment in the long-term disease-free survival in children with EFT has been achieved with the introduction of multimodal therapy that incor-multimodal therapy that incor-porates surgery, chemotherapy and/or radiation therapy [1–3]. However, outcome remains poor for patients who present at diagnosis with high-risk clinical features, and in patients who suffer progressive disease during or following therapy. Several pretreatment factors are predictive of a favorable outcome, including:

• Site: EFT in the distal extremities carrying a better prognosis;

• Size: tumor volume of less than 100 ml;

• Age: infants and children younger than 15 years have a better outcome;

• Gender: females have a more favorable prog-nosis, absence of metastases, and nonelevated lactate levels.

While patients with favorable pretreatment features have an expected overall survival (OS) of more than 65%, patients with unfavor-able features, such as bulky primary tumors,

multifocal or metastatic disease at presentation, complex karyotype (defined as the presence of ≥five independent chromosome abnormalities at diagnosis) and modal chromosome numbers lower than 50 [4], overexpression of the p53 pro-tein and loss of 16q, and refractory or recurrent disease, have a very poor prognosis, with an OS rate at 3 years of only 10–30% [4–10].

Since EFT exhibits a dose-response rela-tionship to chemotherapy, consolidation with high-dose, myeloablative chemotherapy, with or without radiation therapy, followed by autolo-gous hemato poietic cell transplant (HCT) res-cue, represents an option for improvement of event-free survival (EFS), despite the risk of increased toxicity.

RationaleThe concept behind the strategy of high-dose therapy (HDT) followed by autologous hema-topoietic rescue is based on the observation that outcome in many malignancies is dependent on dose intensity. Typically, the dose response for most chemosensitive tumors is steep for both toxic and therapeutic effects [11]. Preclinical studies with experimental, high-growth rate tumor models have documented a linear log cor-relation between dose and tumor cyto toxicity. A three- to ten-fold increase in drug dose, par-ticularly for alkylating agents, may result in a multiple log increase in tumor cell death [11–13]. Myelosuppression is the dose-limiting toxicity

Joseph Rosenthal†1 and Anna B Pawlowska1

1Pediatrics and Pediatric Hematology/Hematopoietic Cell Transplantation, City of Hope, 1500 E Duarte Road, Duarte, CA 91010, USA †Author for correspondence:[email protected]

The prognosis for high-risk Ewing’s tumors has been improved by multimodal radiation and chemotherapy. Ewing’s family of tumors requires risk-adapted treatment. Risk stratification is dependent on stage, tumor localization and volume, and the pattern of disease spread at the time of diagnosis and the time of relapse. The concepts for high-dose therapy followed by hematopoietic cell transplantation in Ewing’s family of tumors are based on dose–response and dose–intensity relationships. This article will discuss the use of high-dose therapy followed by hematopoietic cell transplantation, focusing on recent progress with respect to agent combinations, dose and outcomes of therapy.

Keywords: Ewing’s sarcoma • hematopoietic stem cell transplant • high-dose therapy

High-dose chemotherapy and stem cell rescue for high-risk Ewing’s family of tumorsExpert Rev. Anticancer Ther. 11(2), 251–262 (2011)

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Review Rosenthal & Pawlowska

for alkylating agents, one of the most effective groups of che-motherapeutic agents for ETF. A significant escalation in dose intensity, beyond the dose associated with myeloablation but before the occurrence of any other dose-limiting toxicities, can be achieved with hematopoietic rescue using transfusion of cryopre-served autologous peripheral blood stem cells (PBSCs) collected prior to high-dose chemotherapy [12]. Utilizing transplantation of autologous hematopoietic cells may allow a significant increase in dose intensity, achieving enhanced tumor kill while circumvent-ing the sequelae of severe myelotoxicity. Furthermore, the use of allogeneic HCT may hypothetically add a graft-versus-tumor (GVT) element to the treatment.

Considerations for HDT & HCTSeveral nonrandomized trials have assessed the value of more intensive, time-compressed HDT followed by autologous stem cell rescue, but the level of evidence for benefit, such as those obtained from randomized trials, is lacking [14]. The primary challenge for using this modality is to establish whether it con-fers added value, and if so, under what conditions. Even in cases that are more likely to be responsive to HDT and HCT, the data are based on anecdotal small-series data. Results of large, well-designed randomized studies are still pending. Only a few studies that may answer the open questions, such as the study conducted by the European Ewing Tumor Working Initiative of National Groups Ewing Tumour Studies 1999 (EURO-E.W.I.N.G.99) were published [15]. Results of other studies, including the multi-national study conducted by the EURO-E.W.I.N.G.99 in col-laboration with the Children’s Oncology Group AEWS0331 are still pending.

The fulfillment of certain criteria is required to be eligible for consideration for HDT and HCT. The primary criterion is that the patient suffers from a condition for which there is, at least, some evidence for potential benefit. Other important conditions are:

• The tumor remains chemosensitive at the time of initiation of HCT;

• The patient has adequate organ function to tolerate the impact of HDT;

• An adequate number of hematopoietic progenitor cells have been collected prior to proceeding with HCT.

Several criteria that influence survival rates have been identi-fied as predictors of guarded prognosis, these are: the presence of metastatic disease to the bone or multifocal disease, tumor volume, tumor site, bulky nonresectable primary tumors, and age older than 16 years. Recurrence or progression following frontline therapy is associated with poor prognosis [13]. Patients with guarded prognostic EFT may continue to demonstrate chemotherapy responsiveness, as indicated by the high initial disease response rates, and progression-free intervals observed following conventional-dose chemotherapy. For example, increased but still nonmyeloablative doses of cyclophosphamide or ifosfamide are associated with increased efficacy relative to standard doses [16,17].

What are the disease eligibility criteria for the consideration of HDT followed by HCT?Patients with advanced stage EFT, either with high-risk features at the time of diagnosis or with recurrent metastatic disease, and who have chemosensitive tumors appear to benefit most from this approach. Several groups of patients can be identified as follows.

Recurrent diseasePatients who suffer recurrence of EFT, mostly early recurrence in less than 2 years, constitute the majority of candidates for consolidative therapy with HDT and HCT.

The overall prognosis for patients with recurrent Ewing’s sar-coma is poor; 5-year survival following recurrence is approxi-mately 10–15% [18–20]. Patients who suffer recurrence of more than 2 years from initial diagnosis have a 5-year survival of 30 versus 7% for patients who recur within 2 years [21]. Patients with both local recurrence and distant metastases have a worse outcome than patients with either isolated local recurrence, or metastatic recurrence alone [18,21]. Data from several reports, including the European Intergroup Cooperative Ewing Sarcoma Study (EICESS), demonstrating that patients with relapsed EFT benefit from HDT. This improvement is almost entirely due to the impact of treatment in the group of patients with early relapse (<2 years after diagnosis) who increase their prognosis from 2 to 17% with HDT and HCT, whereas in patients with late relapse (>2 years after diagnosis) there is no significant difference between HDT and conventional therapy [22].

Patients with bone or multifocal metastatic disease at diagnosisThe prognosis for patients with metastases at the time of diagnosis is worse than that for patients with localized EFT. Furthermore, prognosis depends on the site of metastases. Several studies have shown that patients with metastatic spread confined to the pulmonary/pleural space were associated with a fair outcome, while involvement of bone or bone marrow carried a poor prognosis for progression, relapse and death [5,6,23–26]. A large multicenter study shows a 4-year probability of EFS after diagnosis of 27% in patients with disseminated EFT, with improved outcome in patients with isolated pulmonary involvement compared with those with combined pulmonary/skeletal metastases (0.40 vs 0.19; p < 0.05) [27]. While patients with isolated pulmonary metastases at the time of diagnosis are not candidates for HDT followed by HCT, as they have a good prognosis with appropriate therapy (including lung irra-diation with age-dependent doses), this modality may have a role in patients with primary bone and/or marrow metastases, a condition that is almost uniformly fatal, with less than 10% survival at 10 years. This extremely poor prognosis applies to patients with high-risk multiple primary bone metastases alone or in combination with pulmonary disease [25]. Several studies have addressed the potential of HDT with HCT to control primary multifocal EFT, with controversial results [22,28,29]. Future directions may include the combination of local control with radiation and systemic therapy with HDT and HCT [30].

www.expert-reviews.com 253

ReviewHigh-dose chemotherapy & stem cell rescue for high-risk Ewing’s family of tumors

Currently, although based on small series reports and not con-firmed by randomized studies, there appears to be a justifi-cation for HDT followed by HCT in patients with high-risk multiple primary bone metastases alone or in combination with pulmonary disease.

Poorly responsive or refractory primary EFTPoor histological response to preoperative chemotherapy and incomplete or no surgery for local therapy are further adverse prognostic factors. Picci et al. have demonstrated a correlation between complete postchemotherapy necrosis (grade III) and improved EFS compared with patients who have residual dis-ease nodules at the time of surgery (grades I and II) [31]. Bacci et al. reported outcomes in patients treated by surgery (alone or follow ed by radiation therapy). The investigators found a strong correlation between the histological response and EFS. The EFS was 77.2 and 28% (p < 0.001) in good and poor responders, respectively. In patients who relapsed and died from their cancer, the survival time was significantly longer in good responders than in poor responders (51 vs 32.6 months; p = 0.03) [32].

Site of primary tumor when associated with other high-risk featuresThe contribution of the tumor site on prognosis is unclear. Several studies have shown that a primary EFT site in the pelvis was associated with a poor outcome in patients without metastatic disease [5,33–35]. By contrast, a report from the St Jude Cancer Research Center shows no significant differences between pelvic and nonpelvic primaries [36]. Similarly, a report of the German group Cooperative Ewing’s Sarcoma Study (CESS) questions the influence of pelvic tumor site on prognosis [37]. The inferior outcome for patients with pelvic tumors might be explained by large tumor size with extensive soft-tissue invasion and the higher percentage of patients presenting with metastases at diagnosis [13]. At this time, it appears that a localized pelvic EFT, in and of itself, without other risk factors, would not constitute a sufficient indication for HDT and HCT.

Tumor volume, only when associated with other high-risk featuresAlthough the tumor volume is an important prognostic factor, it is not sufficient by itself to constitute an indication for HDT and HCT. Reports from the CESS of the German Society of Pediatric Oncology showed a 3-year EFS of 75% for patients with a tumor volume of less than 100 ml compared with 10% for patients with a tumor volume of 100 ml and above [16,38,39]. More recent analyses show that, with the advent of therapeutic strategies, the prognostic predictive value is best achieved using a cut-off of 200 ml tumor volume. This may reflect improvements in therapy modalities, as well as improved supportive care measures. The 8-year EFS rate of patients with tumors more than 200 ml was 42% compared with 70 and 63% for patients with tumors of 100–200 ml and below 100 ml volume, respectively [37]. Although long-term EFS is inversely related to tumor volume, it does not independently constitute an indication for HDT and HCT.

Selection of agents for HDT General principles in the selection of the appropriate agents for myeloablative chemotherapy are as follows: proven activity against the tumor treated with steep dose–response curves, a regimen con-sisting of agents with nonoverlapping toxicities, and agents with acceptable nonhematopoietic toxicities at myeloablative doses. Alkylating agents share several properties, which make them ideal candidates for HDT regimens. Alkylating agents have been shown to be effective against a large variety of human malignancies. Myelosuppression is the most common dose-limiting toxicity. The nonhematopoietic toxicities vary and are non -overlapping among different alkylating agents, and high doses have been shown to overcome tumor cell resistance.

Melphalan was selected as the primary alkylating agent for myeloablative therapy because of its predominantly hematologic dose-limiting toxicity and its short half-life, allowing transfusion of hematopoietic cells shortly after completion of therapy. It was tested as a single agent for HDT in EFT [40–42], as well as in other tumor models [41,43,44]. Only a few other agents have been investigated in single-agent Phase I or Phase II studies [45], such as etoposide [46], thiotepa [47,48], cyclophosphamide [49] and cis-platinum [50,51], mostly with partial responses in a few patients. Only limited, preclinical data are available to show that busulfan can be active as a single drug in patients with multiple relapsed EFT. In a recent study the cytotoxicity of busulfan and treo-sulfan was tested on several pediatric tumor cell lines, including four EFT lines. In these studies, both treosulfan and busulfan reduced the growth of all tumor cell lines in a time- and dose-dependent manner. Treosulfan was consistently more cytotoxic than busulfan in vitro [52].

Most myeloablative protocols contain high-dose melphalan in combination with etoposide, busulfan, carboplatin, thiotepa or other agents, for which theoretical or preclinical data suggest activity when given in high doses, but documented evidence of efficacy when given as a single agent is lacking [13]. Melphalan is the agent most studied in the context of a single high-dose agent for high-dose chemotherapy followed by autologous hematopoi-etic rescue [40–43]. Most of the reports are of relatively small case series. In a meta-analysis, the doses of melphalan ranged from 120 to 215 g/m2, and the response rates varied between 0.50 and 0.66 [53]. High-dose melphalan given at doses up to 210 mg/m2

yielded six out of eight partial responses in extensively treated patients with relapsed Ewing’s sarcoma [40].

Multiple high-dose combination therapies have been reported. The French Society of Pediatric Oncology (SFOP) has reported results of HDT and autologous HCT in 97 patients with newly diagnosed metastatic EFT. Following standard chemo-therapy, patients received a HD therapy consisting of busulfan 150 mg/m2/day for 4 days followed by melphalan 140 mg/m2. The 5-year OS and EFS were 38 and 37%, respectively [54,55]. The investigators concluded that, compared with conventional chemotherapy, HDT and HCT may have outcome benefits for patients with lung-only metastases or bone metastases [54]. The Italian Association for Pediatric Hematology-Oncology (AIEOP) reported the cumulative results of autologous HCT in which,



after completion of initial treatment, patients were given consolidative ther-apy with busulfan (16 mg/kg), etopo-side (1800–2400 mg/m2) and thiotepa (300 mg/m2) followed by HCT. The regimen appeared feasible, and the 5-year EFS was 44.5% (±7.5%) [56]. The European Bone Marrow Transplant for Solid Tumor Registry (EBMTSTR) has reported results of HDT with autolo-gous hematopoietic rescue in 63 chil-dren with high-risk ES (n = 50) or PNET (n = 13). In total, 32 patients with metastatic disease (22 with metas-tases to bone or marrow) transplanted in first complete response (CR) achieved a 5-year EFS of 21%, while 31 patients transplanted in second CR had a 5-year EFS of 32%. Favorable outcome predic-tors were localized disease at the time of diagnosis and distant rather than localized relapse [57]. Recent reports, presented in the form of meeting pre-sentations, have shown promising results with the use of treosulfan [58,59] for HCT in EFT patients; however, these have not yet been reported in peer-reviewed publications.

No preparative regimen modality has emerged as markedly superior to other approaches (Table 1). While it is possible that end-of-therapy consolidation with HDT and hematopoietic rescue may be beneficial in patients who achieved CR or at least very good partial response, its role as salvage therapy in patients with more advanced disease is questionable.

Most of the historical data cited earlier, is based on reports in selected patients: patients who tolerated several courses of standard chemotherapy well, maintained good organ function, and were able to collect a sufficient number of hematopoi-etic stem cells. In addition, most of the historical reports lack randomization or comparison with adequate controls. Both these factors are limitations of the strength of these reports as evidence-based medi-cine. A prospective, randomized approach with an intent-to-treat analysis is missing to confirm an unequivocal advantage of HDT followed by HCT. Such a study should be designed to evaluate tailored approaches to different subgroups of high-risk patients. Ta

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Single or repeat courses of HDT & HCT The use of a single course of HDT followed by autologous HCT has suggested a favorable impact on outcome com-pared with conventional combination chemotherapy. The feasibility of a single cycle led to the hypothesis that further dose intensification could be achieved using repeat cycles of HDT with autologous HCT. Repeat cycles, also known as tandem transplants, may have several advantages: an increase in the dose intensity of the regimen, by both the addition of chemotherapy and by the opportunity to utilize more chemotherapeutic agents; improved drug delivery by reduction of bulk disease with the first cycle; and induc-tion of cell cycling in cells that were at rest during the first myeloablative therapy. This approach has been reported in a variety of hematological malignancies and solid tumors with variable success [60–65]. Burdach et al. report the largest experience with tandem transplants in patients with EFT using two sequential courses of melphalan and etoposide, each followed by HCT. The OS and EFS rates ± standard deviation at 5 years are 35 ± 9% and 29 ± 9%, respectively [66]. Few other studies have reported experience with tandem transplant. The results are summarized in Table 2.

The few existing studies suggest that alkylating agent-based HDT entails acceptable toxicities despite previous aggressive therapy in patients with high-risk EFT. The studies using myeloablative tandem systemic consolidation may offer a rea-sonable, albeit still unsatisfactory, rate of long-term OS and EFS, with acceptable toxicity in most patients with advanced EFT. In one study, only 65% of the patients were able to proceed to a second cycle of treatment, mostly owing to dis-ease recurrence in the interval between the two courses [67]. Prospectively designed studies are needed for the evaluation of the optimal approach for HDT followed by HCT; primarily, multiple cycles versus augmentation of a single cycle.

Preparative regimens containing radiation The rationale for utilizing total-body irradiation as an ele-ment of HDT was tested in several clinical observations. Results were variable; while a few reports showed favorable outcomes [28,68–72], others showed increased treatment-related morbidity and mortality, resulting in no overall benefit [66,73,74]. Furthermore, updated long-term reports regarding patients with initial favorable outcomes, specifi-cally in patients with localized tumors, were only marginally better than standard chemoradiotherapy (Table 3) [13,72,75].

Of special interest is the report from the Children’s Cancer Group by Meyers et al. [74]. Only 23 out of 30 enrolled patients (77%) were able to start HDT due to either dis-ease progression or toxicity. Using a regimen consisting of melphalan, etoposide and total-body irradiation (TBI) with HCT support, the EFS at 2 years post-HDT for the 23 patients who received consolidative treatment was 24%. The majority of the patients who underwent high-dose con-solidation therapy experienced relapse and died with progres-sive disease. Three patients (13%) died of treatment-related Ta

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Ove

rall

surv

ival

; TB

I: To

tal-

bo

dy

irra

dia

tio

n; T

hio

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MI:

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mortality (TRM) [74]. The authors concluded, that this strategy did not improve prognosis for this group of patients. This study has put in doubt not only the role of TBI-containing HDT, but also the role of HDT followed by HCT in general for the treatment of patients with EFT with primary metastases to bone or bone marrow [76]. Comparisons between TBI and non-TB-based HDT protocols have been presented by a few investigators. The European Bone Marrow Transplant Solid Tumor Registry (EBMT-STR) reported the cumulative results of HDT and HCT for EFT in Europe for two time periods. The first reported on 63 children with high-risk EFT enrolled between December 1982 and November 1992 [57] and the second on 281 patients enrolled from 1999 to 2005 [15]. In the first report, the HDT regimens were grouped into six categories: four non-TBI-based and two with TBI. No specific protocol emerged as the preferred regimen; however, patients treated with HDT containing busul-fan had a favorable outcome when compared with TBI-containing regimens [57]. Of particu-lar interest, all four patients treated for meta-static bone disease with busulfan-containing regimens survived, while only one out of ten patients treated with TBI-containing regimens survived 5 years after HDT [57]. In the sec-ond and larger report, the HDT consisted of a combination of busulfan and melphalan. Of 281 patients enrolled in the study, 169 (60%) were able to proceed with HDT followed by autologous HCT. While the 3-year EFS and OS for the whole group was 27% (±3%) and 34% (±4%), respectively, patients who proceeded with HCT had a 3-year EFS of 45% (±3%). The 3-year EFS rates for patients in CR were 57% (±10%), with 32% (±5%) for patients in PR, and 24% (±7%) for patients with stable or progressive disease (p = 0.017) [15]. Risk fac-tors for poor outcome comprised of age older than 14 years, a primary tumor volume of over 200 ml, more than one metastatic site, and bone or bone marrow metstases [15]. In a collaborative study (Meta EICESS [MetaEICESS]) Burdach et al. compared a tandem non-TBI-based HDT with HCT regimen (TandemME), to a single, TBI-based regimen (hyper-melphalan/etopo-side [HyperME]). Among 54 eligible patients, 26 were treated according to the HyperME protocol and 28 were treated according to TandemME protocol. The EFS was 22% (±8%) in the TBI-based HyperME regimen and 29% (±9%) in the non-TBI, TandemME, Ta

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regimen. The TRM rate was 23% in HyperME and 4% in TandemME. The conclusion was that the outcome of the non-TBI approach appeared to be superior to the TBI-based approach [66].

In summary, attempts to use TBI-containing HDT regimens for treatment of advanced EFT have shown mixed results, and have generally failed to demonstrate an advantage over standard therapies. The increased toxicity associated with TBI may not be offset by the potential benefits. The role of radiation as an effective therapy in EFT is well documented; however, the dose conventionally applied with TBI or total-marrow irradiation [77] is below the threshold for eradication of EFT cells, considered to be approximately 40 Gy, while toxicity to bystander tissues is significant. The potential role of intensity-modulated radiation therapy, including the use of helical tomotherapy as an additional element in a course of HDT, has yet not been fully explored; how-ever, a potential benefit may exist by delivering systemic and local control simultaneously. A potentially powerful novel approach combining systemic therapy with local control measures using total-body MRI-governed involved-compartment irradiation with HDT and HCT rescue showed an improvement in long-term sur-vival in patients with multiple primary bone metastases [30]. The coadministration of systemic therapy utilizing HDT followed by HCT and local disease control deserves further investigation.

PurgingAn inherent disadvantage of utilizing autologous hematopoietic cells in HCT is the risk of contamination with tumor cells. The advent of molecular genetic tools enables the detection of minimal residual disease. The role of tumor cells contained in the stem cell graft in post-transplant recurrence of disease is unclear. Investigators from the St Jude Children’s Research Hospital have used gene-marking techniques to investigate the mechanism of relapse and biology of reconstitution following autologous bone marrow transplanta-tion. They used a retrovirus-mediated transfer of the neomycin-resistance gene to mark bone marrow harvested and subsequently reinfused in patients with neuroblastoma (n = 8) or acute myeloid leukemia (n = 12) in clinical remission. Their studies show that autologous bone marrow transplantation may contain tumor cells possibly contributing to relapse [78,79]. The presence of microme-tastases has been shown by investigators from Duke University to be associated with reduced EFS and OS in the setting of HDT followed by hematopoietic rescue [80]. Leung et al. demonstrated a high incidence of cell contamination in marrow and PBSCs col-lected from patients with neuroblastoma and EFT prior to HCT [81]. They reported that no tumor cells were detected in the marrow by clinical histology immediately before marrow or PBSC harvests. However, 82% of PBSCs and 89% of back-up marrow harvests were contaminated with tumor by reverse-transcriptase (RT)-PCR and/or immunohistochemistry assays [81]. Thomson et al. examined the assumption that PBSCs collected after an aggressive course of therapy can be purged of residual tumor cells in vivo. They used RT-PCR to evaluate 122 samples of peripheral blood, marrow and PBSCs collected from 12 pediatric patients with metastatic EFT or alveolar rhabdomyosarcoma. Molecular evidence of tumor con-tamination was detected in one out of 40 PBSCs collections from

12 patients. Clearance of disease by RT-PCR was documented in all patients. The conclusion was that aggressive chemotherapy appears to be effective in removing tumor cells from PBSCs, marrow and peripheral blood as detected by RT-PCR. Vermeulen et al. have shown that tumor cell contamination of PBSC collection is rare and does not seem to be associated with an unfavorable outcome [82]. They tested tumor contamination by RT-PCR in 88 patients who underwent HDT followed by PBSC HCT. Seven out of 88 PBSC collections (8%) contained tumor cells. In total, 45 patients relapsed with a median time of 15 months after graft, only four of whom had tumor cell contamination of the PBSC harvest [82].

A variety of physical, pharmacological and immunological approaches to remove residual tumor cells from the graft have been explored. Although a marked tumor kill in the range of 4–6 log has been achieved, no significant differences in relapse rate, EFS or OS between patients who received purged or nonma-nipulated grafts have been demonstrated [83–85]. Although con-cerns regarding the possibility of tumor contamination in the graft have not been alleviated, it appears that at this time there are no indications for purging of autologous PBSC after collection.

Local disease control after completion of HDT & HCTHigh-dose therapy followed by HCT should be viewed as a link in a chain of events that needs to be well orchestrated. While theo-retically providing a reasonable means of consolidation in terms of systemic control, it is critical to maintain adequate local control to prevent recurrence since local failures are associated with poor prognosis. Therefore, adequate local therapy is essential for long-term survival. Local treatment modalities in EFT consist of surgery and radiation therapy. In the UK Children’s Cancer Study Group (UKCCSG), local recurrence rate was 27% for radiotherapy alone and 11% for surgical resection [34]. In the CESS trials, the recur-rence rate for local recurrence and systemic metastasis was lower after surgery with or without irradiation compared with definitive irradiation alone (7 and 31%, respectively) [86]. A report from the Italian Cooperative Study showed that the frequency of local recur-rences was similar after surgery (7%), radiation therapy (7%), and combined surgery and radiotherapy (6%) [87]. The optimal timing of local control measures remains an unanswered question. In our patients, we elect to proceed with surgery, when indicated, after a few courses of standard chemotherapy. We defer radiation due to concerns of pulmonary toxicity with rebound phenomenon to the earliest time possible, usually within 4–6 weeks after HCT.

Allogeneic HCTAllogeneic transplants have been attempted in advanced EFT tumors to minimize the risk of contamination and to introduce the element of GVT effect [13]. An immune-mediated effect against sar-coma cells has been shown in experimental animal models of allo-geneic transplantation [88]. Only small series and single case reports in patients with EFT have been reported on allogeneic HCTs from HLA-matched sibling or haploidentical donors. One series, includ-ing nine patients with various histotypes, has shown no evidence of cancer regression following allografting [89], while other authors have reported some evidence of a GVT effect [90,91]. In the largest



series to date, Burdach et al. compared outcomes after autologous and allogeneic HCT to evaluate the potential therapeutic benefit of GVT in patients with advanced EFT. In total, 26 out of 36 patients were treated with autologous HCT and ten with allogeneic HCT. The 5-year EFS was 25 ± 8% after autologous and 20 ± 13% after allogeneic HCT. Incidence of TRM was more than twice as high after allogeneic (40%) compared with autologous HCT (19%). In this study, the outcome was not improved by allogeneic HCT, which may be due its higher transplant-related mortality; however, the group was too small to draw conclusions regarding the potential benefit from the GVT effect [92]. Only a limited number of other peer-reviewed reports have been published [90,91]. With the intro-duction of reduced-intensity conditioning regimens, it is intriguing to speculate that the decreased TRM expected with this modality will result in improved outcomes, but proof of concept is still lack-ing. As allogeneic HCT for EFT is still considered an experimental approach, the patients enrolled on clinical trials tend to suffer from more advanced disease compared with patients treated with HDT and autologous HCT; therefore, a meaningful evaluation of the role of this modality awaits further investigation.

Allogeneic haploidentical natural killer cell transplantNatural killer (NK) cells are cytotoxic lymphocytes directed against tumor and virus-infected cells. Activity of NK cells is controlled by a balance between inhibitory and activating signals. Inhibitory signals are provided by human leukocyte antigen (HLA) class I molecules, which either bind to killer immunoglobulin-like receptors (KIR) or NKG2A/CD94 on NK cells. These inhibitory signals are coun-teracted by activating signals, provided by several receptor–ligand combinations. The best characterized activating NK-cell receptors are NKG2D and DNAM-1 [93]. In a preclinical study, Verhoeven et al. demonstrated that ES cells were recognized and lysed by rest-ES cells were recognized and lysed by rest- cells were recognized and lysed by rest-ing and, with higher efficacy, by IL-15-activated NK cells from healthy donors. The lysis of ES cells by NK cells was dependent on the activating NK-cell receptors NKG2D and DNAM-1, whose ligands are commonly expressed by ES cell lines and pri-ES cell lines and pri- cell lines and pri-cell lines and pri- and pri-mary Ewing’s tumor cells. At diagnosis and prior to chemotherapy, patients suffering from Ewing’s sarcoma display reduced NK cell cytotoxicity, despite normal numbers of NK cells and adequate NKG2D expression [93]. Clinical reports concerning haploidenti-cal transplants for pediatric solid tumors are still anecdotal, and a potential GVT effect in such cases has been suggested [91,94,95]. A few cases have described the use of allogeneic haploidentical NK cell transplants all in patients with advanced disease after failure to

respond to multiple previous courses of chemotherapy. Partial and transient responses have been documented [95,96]. Pilot studies are ongoing, further exploring this modality.

Expert commentary In contrast to allogeneic HCT or other therapeutic cellular thera-pies where the treatment is curative in and of itself, HDT followed by autologous HCT for solid tumors should be regarded as a restorative/supportive treatment tool that allows the delivery of potentially curative, high-dose myeloablative therapy.

The role of HDT followed by autologous HCT in patients with EFT is still debatable. Multiple reports, mostly retrospective, are pointing towards a favorable long-term outcome in patients with advanced disease compared with standard therapies; however, further information, such as that expected from the multinational study currently underway, is needed. With the current data, the use of this modality is justified in a selected group of patients with primary metastatic disease or recurrent disease.

Five-year view Ongoing progress in three areas will determine the future use of HDT in combination with HCT as part of the treatment of advanced, high-risk EFT:

• Improvement in diagnostic tools, including better understand-ing of molecular and genetic markers will enable optimal selec-tion of patients with advanced EFT who may benefit most from this modality;

• The prospects are high for better identification of the optimal HDT components, including the most effective chemotherapy agents and the inclusion of intensity-modulated radiation therapy, such as the use of helical tomotherapy;

• Rapid progress in the field of cellular therapeutics will enhance our ability to offer immune-based cellular therapies, including allogeneic HCT, for selected groups of patients with high-risk EFT.

Financial & competing interests disclosureThe authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• Multiple reports, mostly retrospective series reports, are pointing towards a favorable long-term outcome in patients with advanced disease compared with standard therapies.

• Strong evidence is still missing regarding the role of high-dose therapy (HDT) followed by autologous hematopoietic cell transplantation (HCT) in patients with Ewing’s family of tumors.

• At present, the preferred HDT appears to be alkylating agent-based, mostly including melphalan. Attempts to use total-body irradiation-containing HDT regimens have shown mixed results, and generally failed to demonstrate any advantage.

• The role of adding intensity-modulated radiation therapy, including the use of helical tomotherapy, has theoretical merits that require further investigation.

• At present, immune-mediated cellular therapies, including allogeneic HCT, are still under investigation.



ReferencesPapers of special note have been highlighted as:•ofinterest••ofconsiderableinterest

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high-dose chemotherapy and stem cell rescue for high-risk ewing’s family of tumors

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