Introduction

Autologous stem cell transplantation (ASCT) has been employed as consolidation therapy for children with a variety of high-risk solid tumors.^{1, 2} The rationale for this approach is that many of these tumors are sensitive to chemotherapy and radiation, but because of steep dose–response curves to both treatment modalities, relatively small dose reductions can result in sharp decreases in log tumor cell kill.³ Phase I and II studies have demonstrated the activity of high-dose melphalan against tumors refractory to intensive conventional chemotherapy.^{4, 5} The dose-limiting toxicity of alkylating agents such as melphalan, busulfan and thiotepa is myelosuppression. This problem can be circumvented by rescue with ASCT, thereby allowing a 3–10 fold dose escalation of those agents.^{6, 7}

We have previously reported our experience in two consecutive studies evaluating the role of myeloablative chemotherapy followed by ASCT in children and young adults with high-risk solid tumors.⁸ Here, we present an update on 11 of those previously reported patients and a further cohort of 25 patients treated on a subsequent study at the University of Minnesota. We have found that high-dose alkylating agent therapy followed by ASCT results in a better than expected survival for patients with high-risk Ewing's sarcoma (ES) and desmoplastic small round cell tumor (DSRCT), but little apparent benefit for patients with other diagnoses. We confirm our previous finding that disease status at the time of ASCT is an important predictor of outcome with those being transplanted in complete remission (CR) having superior survival.

Methods

Patients

A total of 36 patients with high-risk solid tumors were treated on two consecutive autologous transplant protocols (MT9408 and MT9713) at the University of Minnesota between May 1995 and March 2004. Patients with a range of high-risk solid and brain tumors who had achieved a CR or partial response with non-progressive disease were eligible. Patients had high-risk tumors that were either metastatic at diagnosis or had relapsed following therapy. Adequate organ function was documented. Demographic characteristics are presented in Table 1 and specific disease characteristics and treatment details are presented in Tables 2 and 3.

Table 1 - Patient characteristics.

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Table 2 - Disease characteristics and treatment details of Ewing's sarcoma patients.

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Table 3 - Disease characteristics of non Ewing's sarcoma patients.

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Signed informed consent approved by the University of Minnesota Committee on the Use of Human Subjects in Research was obtained from parents, legal guardians or patients as appropriate. Clinical and laboratory data were retrieved from patient charts and the University of Minnesota Bone Marrow Transplant database that prospectively collects data on all patients.

Conditioning regimen

The conditioning regimen was identical for the two protocols except that patients treated on MT9713 also received the chemoprotectant amifostine. The chemotherapy schedules and dosages are outlined in Table 4. The 12 patients who were transplanted after December 1999 received intravenous rather than oral busulfan (dose: 4 mg/kg i.v. daily in divided doses for 3 days if <4 years old or 3.2 mg/kg i.v. daily in divided doses for 3 days if >4 years old). Stem cell source was peripheral blood stem cells (PBSC) in 20 patients, autologous bone marrow in 15 patients and syngeneic bone marrow in one case. A minimum of 10⁸ nucleated cells per kilogram was infused. G-CSF-mobilized PBSC collection failed to yield an adequate cell dose in six patients, all of whom subsequently had autologous bone marrow harvested. Purging of stem cell products was not performed.

Table 4 - Conditioning regimen.

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Supportive care

Phenytoin was administered during busulfan therapy (starting 24 h before the first dose and continuing for 24 h after the last dose). Patients were all hospitalized in single rooms with high-efficiency particulate air filtration until neutrophil recovery. G-CSF (5 g/kg) was administered beginning on the day of infusion until absolute neutrophil count (ANC) was greater than 2.5 10⁹/l on each of the two consecutive days. CMV and HSV seropositive patients received acyclovir as prophylaxis against reactivation until day +100. Blood product support included transfusion of packed red blood cells to maintain Hb greater than 8 gm/dl and platelets to maintain counts greater than 10 10⁹/l.

Post transplant therapy

Selected patients received radiation therapy following ASCT. Specifically, two patients with ES and pulmonary metastases who had not previously been treated with whole lung irradiation received 1800 cGy and all patients with DSRCT received abdominal radiation (3600 cGy) based on disease location.

Statistical analysis

Data regarding transplant patient characteristics, post transplant complications and outcomes were prospectively collected by the Biostatistical Support Group at the University of Minnesota. The Kaplan–Meier product limit method was used to estimate survival and the log rank statistic was used to complete comparison between groups.⁹ Patients were censored at the time of last follow-up. Cumulative incidence was used to estimate neutrophil engraftment.¹⁰ Time to neutrophil engraftment was measured from transplant to the first of three consecutive days with an ANC >0.5 10⁹/l.

Results

Engraftment

All patients achieved engraftment. The median time to neutrophil engraftment was 11 days (range 9–56 days). There was no significant difference in engraftment between MT9408 and MT 9713 (P=0.15). Data on platelet engraftment was only available for 21 patients. The median time to platelet engraftment (defined as the first of three consecutive days with an unsupported platelet count >50 10⁹/l) was 43 days (range 19–102 days).

Regimen-related toxicity and post transplant complications

Regimen-related toxicity and post transplant complications are summarized in Table 5. There were two early deaths attributable to regimen-related toxicity. Both patients were treated on protocol MT9408. Deaths occurred on days +19 and +36 and both patients had hepatic veno-occlusive disease complicated by multi-organ failure. One of the patients also had documented candidemia. In all, 13 patients (36%) had at least one documented episode of bacteremia all of which were successfully treated with parenteral antibiotics. In all, 10 patients (27%) developed cutaneous varicella zoster following ASCT and two patients (6%) developed CMV viremia which was treated pre-emptively with ganciclovir. These patients did not develop evidence of CMV disease. Grade IV mucositis necessitating parenteral nutrition and analgesia was almost universal. Two patients developed hemorrhagic cystitis which resolved with supportive therapy. One patient suffered a seizure which was attributed to amifostine-induced hypocalcemia.

Table 5 - Transplant-related complications.

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Outcome

There are 14 surviving patients as of November 30, 2004; 13 are disease free. Median follow-up among survivors is 3.5 years (range 0.6–7.9 years). Overall survival (OS) estimate at 1 year following transplant is 63% (95% CI: 47–79%) and at 3 years, 33% (95% CI: 16–50%) (Figure 1). The group of survivors includes 8/16 patients with a diagnosis of ES, 4/4 patients with a diagnosis of DSRCT and one patient with an ovarian small cell carcinoma. OS estimates for the group of patients with tumors characterized by translocations involving EWS (ES/DSRCT) were 69% (95% CI: 49–89%) at 1 year and 54% (95% CI: 29–79%) at 3 years which was significantly better when compared to all other diagnoses where the 3-year OS estimate was 13% (95% CI: 0–29%; P=0.03) (Figure 2). The 3-year OS estimate for patients transplanted in CR was 48% (95% CI: 24–72%) as opposed to 12% (95% CI: 0–33%) for those transplanted in partial remission (PR) (P=0.03) (Figure 3). Among patients with a diagnosis of ES/DSRCT, 3-year OS estimate for those transplanted in CR was 76% (95% CI: 57–100%), whereas for those transplanted in PR, 3-year OS estimate was 27% (95% CI: 0–68%; P=0.08). There were no significant differences in OS estimates when patients were compared by protocol (P=0.91), time from diagnosis to ASCT (<1 year or 1 year) (P=0.18) or their indication for transplant (metastatic at diagnosis or relapsed disease) (P=0.57).

Figure 1.

Overall survival. Tick marks indicate surviving patients.

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Figure 2.

Overall survival. Patients with Ewing's sarcoma or DSRCT (solid line) compared to all other diagnoses (dashed line). Tick marks indicate surviving patients.

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Figure 3.

Overall survival. Patients transplanted in complete remission (CR) (solid line) compared to those transplanted in partial remission (PR) (dashed line). Tick marks indicate surviving patients.

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Discussion

The role of myeloablative chemotherapy followed by ASCT as a consolidation therapy for high-risk pediatric solid tumors is yet to be conclusively determined for the majority of histological types. A large cooperative group study has demonstrated a benefit using this approach for children with stage IV neuroblastoma.¹¹ There are limited case reports and series that have illustrated the potential utility of this approach in a wide variety of solid tumor types including Wilm's tumor,^{12, 13, 14} hepatoblastoma,¹⁵ retinoblastoma,^{16, 17} DSRCT,¹⁸ osteosarcoma¹⁹ and rhabdomyosarcoma.²⁰

Of all the solid tumors where this approach has been tried, ES has been the most extensively studied. Recently, the addition of ifosfamide and etoposide to induction chemotherapy significantly improved survival in patients with localized ES.²¹ However, this change did not alter the prognosis for patients with metastatic disease at diagnosis whose OS at 8 years remains very poor at around 30%. Patients with pulmonary metastases had a slightly better prognosis with OS at 8 years of 41% in this study.²² Patients with bone and marrow metastases represent a particularly poor prognostic group with a 10-year EFS in the order of 15%.²² All patients with ES reported in our series received ifosfamide and etoposide as part of their initial therapy. Patients with relapsed disease also have a poor prognosis.²³ One retrospective review of 71 patients with recurrent ES determined that the probability of 5-year post-recurrence survival (PRS) was 17.7% (95% CI: 13–22%). Better outcomes were seen in those patients with recurrence >2 years from initial diagnosis (5-year PRS 35% (95% CI: 27–44%)), those with local recurrence alone who were able to undergo salvage with radical surgery (5-year PRS 31% (95% CI: 20–42%)) and those with isolated pulmonary recurrence who were treated with pulmonary irradiation (5-year PRS 30% (95% CI 18–42%)). Patients in this retrospective review were treated with a combination of multi-agent salvage chemotherapy, surgery and radiation highlighting the fact that cure can be achieved with salvage chemotherapy without the use of ASCT.²⁴ More recently, Barker et al. reported their results of treatment of 55 consecutive patients with recurrent ES. The 5-year PRS for all patients was 23% (95% CI: 11–35%). They confirmed response to salvage chemotherapy and relapse-free interval >24 months as positive prognostic factors. In all, 13 patients received ASCT as part of their salvage therapy. Multivariate analysis demonstrated that reduced risk of death was associated with receiving ASCT (relative risk, 0.26; 95% CI: 0.08–0.85).²⁵

Given the facts that (1) attempts to intensify conventional chemotherapy have not improved outcome, (2) in vitro data demonstrate sensitivity to melphalan and (3) alkylating agents have steep dose–response curves, there has been considerable interest in the use of ASCT as consolidation therapy for these high-risk patients. Kalambakas et al.²⁶ recently published a comprehensive review of the literature which highlighted the conflicting findings regarding the usefulness of this approach. Burdach et al. reported 3-year DFS rates of 45% which they compared to historical controls who had 3-year DFS rates of 2%.²⁷ European registry data analyzing 259 patients receiving autologous transplants for high-risk ES demonstrated a potential benefit for busulfan-containing conditioning regimens with a 54% (95% CI, 49–59%) 5-year progression-free survival compared to 26% (95% CI, 22–30%) for other regimens.²⁸ The Meta European Intergroup Cooperative Ewing Sarcoma Study (Meta EICESS) have published results comparing two consecutive protocols for ASCT in ESFT patients with bone or bone marrow metastases at diagnosis, early (<24 months) relapse or multiply relapsed patients. They reported an EFS rate of approximately 25% (95% CI, 17–33%) for both regimens, a single ASCT with melphalan, etoposide and TBI conditioning or tandem ASCTs with melphalan and etoposide conditioning. The TBI-containing regimen resulted in significantly more toxicity.²⁹

It has been difficult to compare studies because of inconsistencies in the definition of high-risk ES, differences in cytoreductive regimens and the fact that there is a paucity of prospective studies meaning that survival data is often reported only for patients who actually reached ASCT.^{26, 30} Meyers et al. attempted to address some of these problems by prospectively studying the role of ASCT in all ES patients who presented to their institution with bone or marrow metastases at the time of initial presentation. They found no improvement in survival in patients who received ASCT after conditioning with high-dose melphalan, etoposide and TBI compared to historical controls who had received identical induction chemotherapy.³¹ The prospective design of this study enabled the authors to address the issue of selection bias which compromises most of the published reports regarding ASCT for ES. Of the 32 patients enrolled on the study, only 22 (69%) proceeded to ASCT.³²

In our study 8/16 patients with ES remain disease free with a median follow-up of 3.7 years (range: 0.6–7.9 years) post-ASCT. Four of these patients were classified as high risk because they had pulmonary metastases at diagnosis. One patient had pulmonary and marrow metastases at diagnosis. Two patients were treated following pulmonary relapse (at 13 and 27 months following initial diagnosis) and the eighth patient was considered high risk because of a large pelvic primary tumor. We acknowledge that our study is limited by the fact that survival data can only be presented for a group of patients who were referred for transplant (selection bias) and by small numbers. However, the data do demonstrate that the toxicities associated with this conditioning regimen are tolerable and demonstrate encouraging survival rates for this high-risk group of patients suggesting that further investigation of this approach is warranted. It is conceivable that ASCT may benefit patients with lung metastases at diagnosis or relapse proportionately more than those with bone or marrow metastases. A consortium of the majority of European national co-operative groups have designed a study (EURO-E.W.I.N.G.99) in which patients with pulmonary metastases only at diagnosis or poorly responding localized tumors are randomized to receive either consolidation chemotherapy and pulmonary irradiation or busulfan, melphalan followed by ASCT. This trial is ongoing but will hopefully provide a definitive answer regarding the role of ASCT for this group of patients. It should be noted however that, in contrast to our series, patients on this study will not receive whole lung irradiation if they are randomized to ASCT.

DSRCT is a highly malignant small round blue cell tumor of the abdomen that is characterized by a balanced translocation, t(11;22)(p13;q12) which results in an EWS-WT1 fusion product.³² It was first described in 1991 and a literature review in 1996 documented 101 reported cases.^{33, 34} Of those 101 cases, there were only seven surviving patients. DSRCT are generally chemosensitive but responses are short lived. Aggressive surgical resection forms an important part of attempts at curative therapy. There are few reports of the role of ASCT in this disease. Kushner et al.¹⁸ presented a series of 12 patients who were enrolled prospectively and were planned to receive intensive alkylator-based therapy, attempted surgical resection, whole abdomen radiation and ASCT. Seven of 12 patients achieved a CR and at the time of report five remained in CR 9–38 months from diagnosis. Only four patients actually received ASCT, two in CR and two in PR. The patients who were in CR remain so, whereas the other two patients progressed.¹⁸ Kurre et al.³⁵ have reported the use of dose-intensive chemotherapy with PBSC support in three patients who achieved durable remission. Our series presented here includes four patients with a diagnosis of DSRCT all of whom remain alive at the time of reporting. Median follow-up among these patients is 3.2 years (range: 1.1–6.4 years). One older patient (20 years at diagnosis) relapsed 274 days post ASCT but remains alive 1.1 years post ASCT. All patients were treated with multimodal therapy including intensive induction chemotherapy, aggressive surgery aimed at achieving CR, abdominal radiation and ASCT. Given previous reports of very poor prognosis our data supports the use of aggressive multimodal therapy incorporating ASCT for this disease.

Our data demonstrate that patients transplanted in a clinical and radiological CR have superior outcomes than those transplanted in PR. For the purposes of this study CR was defined as no radiological abnormality or histological evidence of disease. It should be noted that patients who were transplanted in PR and are survivors were all patients with primary pelvic ES who had received irradiation but were unresectable. Residual imaging abnormalities in this context should not preclude ASCT. However, other than the above patients (unresected, pelvic tumors), all patients with residual radiographic abnormalities prior to transplant ultimately relapsed.

In conclusion, we present our experience with a series of 36 pediatric and young adult patients who underwent ASCT for high-risk solid tumors at our institution. This alkylating agent intense conditioning regimen had acceptable toxicity despite either previous or subsequent whole lung radiation in selected patients. Patients with ES and DSRCT had better than expected survival. Results for patients with other diagnoses were disappointing but are limited by small numbers. We suggest that our results support the need for larger prospective trials examining the role of ASCT in high-risk ES.

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Acknowledgements

This work was supported in part by a grant from the Children's Cancer Research Fund.