Annals of Oncology Advance Access originally published online on June 16, 2006
Annals of Oncology 2006 17(8):1301-1305; doi:10.1093/annonc/mdl108
© 2006 European Society for Medical Oncology
High dose chemotherapy with bone marrow or peripheral stem cell rescue is an effective treatment option for patients with relapsed or progressive Ewing's sarcoma family of tumours
Department of Oncology, UCL Hospitals NHS Foundation Trust, London, UK
* Correspondence to: Dr J. S. Whelan, The Department of Oncology, 1st Floor Central, UCL Hospitals NHS Foundation Trust, 250 Euston Road, London NW1 2BU, UK. Tel: +44 207 380 9346; Fax: +44 207 380 6952; E-mail: jeremy.whelan{at}uclh.org
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Abstract |
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Background: The outcome for patients with recurrent or progressive Ewing's sarcoma family of tumours (ESFT) is poor. High dose therapy (HDT) has been used for a number of years in an attempt to improve survival; however, evidence for the efficacy of this treatment remains limited.
Patients and methods: Between 1992 and 2004, 33 patients with recurrent or progressive ESFT were treated with HDT with bone marrow (n = 2), peripheral blood stem cell (n = 30), or bone marrow and peripheral blood stem cell support (n = 1), at a single institution. HDT was with busulphan and melphalan in 22 patients; melphalan and etoposide in seven patients, three with total body irradiation (TBI); melphalan in three patients (2 with TBI), and busulphan and cyclophosphamide in one patient.
Results: The 2 and 5 year event free survival was 42.5% (95% CI, 26–59%) and 38.2% (95% CI, 21–55%) respectively. There was one treatment related death from colitis, and grade 4 infection was observed in two patients.
Conclusions: Long-term survival can be attained in patients with recurrent or refractory ESFT treated with HDT. However, this treatment is associated with severe toxicity. A need remains for prospective randomised clinical trials of HDT in this group of patients.
Key words: Ewing's sarcoma, high dose therapy, PNET
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introduction |
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Over the last few decades the prognosis of patients with newly diagnosed Ewing's sarcoma family of tumours (ESFT) has improved significantly, so that 60–70% of patients with localised disease can expect to become long-term survivors. The prognosis remains poor, however, for patients with metastases at diagnosis, or those with large tumours (
200 ml) or tumours with poor response to initial chemotherapy [1
–4]. The role of high dose therapy (HDT) as part of first line treatment in these groups is currently being explored within a large randomised study by the Euro-Ewing's study group [5].
For patients with recurrent or progressive disease after first line therapy, prognosis is similarly poor, with a 5-year survival of between 0 and 20% [6–8]. Factors associated with improved survival after relapse include: relapse more than 2 years from initial diagnosis, relapse confined to lung or local recurrence, and aggressive local treatment to the site of recurrence [6–9]. Survival for patients treated with HDT for recurrent disease has been reported in small series as being between 10 and 45% [10–13]. However the evidence for any benefit of this treatment remains limited.
The purpose of this report is to describe the survival and outcome of a consecutive cohort of patients with recurrent or progressive ESFT, treated with HDT at a specialist centre over a 13-year period.
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patients and methods |
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Between 1992 and 2004, 33 patients with relapsed or refractory ESFT were treated with HDT as part of second line treatment. The patient characteristics are shown in Table 1. First presentation had been with localised disease in 22 patients and metastatic disease in 11. First line treatment was with ifosfamide and doxorubicin based regimens in all but two patients. Local treatment was with surgery alone in 13 patients, radiotherapy in 11, and combined surgery and radiotherapy in nine. Seven patients were treated with HDT as part of salvage treatment for progressive disease during first line treatment, and 26 for relapsed disease. The median time to first relapse or progression was 22.6 months (range, 2–274). The site of first recurrence or progression was local in 11 patients, metastatic in 18, and combined in four. All pathology had initially been reviewed by a review pathologist, and the diagnosis made on the basis of immunocytochemical markers, including CD99 (MIC 2), CD45 (LCA), S100, Desmin, Synaptophysin and MNF 116. Tumours were not routinely investigated for EWS chromosomal rearrangements. Recurrence was confirmed by biopsy where possible.
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To be considered eligible for HDT, patients had to have disease responsive to second line treatment. Other criteria included: adequate organ function, defined as glomerular filtration rate
40 ml/min/1.73m2 (assessed by EDTA); cardiac ejection fraction >45% (when measured by radionuclide angiography) or fractional shortening >28% (when measured by echocardiogram); normal full blood count and liver function; WHO performance status 
2; and written informed consent. At initial relapse or progression all patients underwent full re-staging, including computed tomography (CT) of the chest, chest x-ray, technetium-99 bone scan with additional imaging of abnormal sites, bilateral bone marrow aspirates and trephines, and standard radiographs and magnetic resonance imaging (MRI) for local recurrence where appropriate. All positive sites were reassessed prior to HDT.
chemotherapy
Patients were initially treated with induction salvage treatment until remission was achieved or there was no further response. Second line chemotherapy was with cyclophosphamide, carboplatin and etoposide in 10 patients [14], ifosfamide based regimens in 21 patients, and other regimens in two (Table 1). Differing induction regimens were selected according to an evolving practice and were dependent on time from completion of first line therapy. The best response prior to HDT was: complete remission (CR) in 14 patients; partial remission (PR), defined as 50% decrease in the sum of perpendicular diameters of all target lesions, in 10 patients; minor response defined as > 25% but <50% reduction of tumor volume in seven patients, stable disease in one patient and progressive disease in one patient. This latter patient developed new but operable lung metastases at the end of first line treatment, and was therefore deemed suitable for HDT.
high dose therapy
HDT was with busulphan 600 mg/m2 (<60 kg) or 16 mg/kg (60 kg) and melphalan 140 mg/m2 in 22 patients; melphalan 120–140 mg/m2 and etoposide 60 mg/kg in seven patients, three with total body irradiation (TBI); melphalan 140–200 mg/m2 in three patients (two with TBI) and busulphan 16 mg/kg and cyclophosphamide 60 mg/kg in one. One patient received a double graft, with two courses of melphalan 135 mg/m2 and etoposide 60 mg/kg. Different regimens again reflected evolving practice in response to published data [15, 16]. Two patients received autologous bone marrow, one patient autologous bone marrow and stem cells, 29 patients autologous peripheral blood stem cells, and one patient received an allogenic bone marrow transplant due to an unsuccessful autologous harvest. All procedures required baseline collection of at least 2 x 106/kg CD34 cells, and GM-CFC 20 x 104/kg for reinfusion. After 1997 all patients received granulocyte-colony stimulating factor (G-CSF) following re-infusion of stem cells (n = 22).
surgery/radiotherapy
Fourteen patients had resection of disease at the site of progression/recurrence prior to HDT (four of whom had remaining disease elsewhere). Two further patients underwent surgery to the site of recurrence following HDT, and three patients received definitive radiotherapy to the site of relapse after resolution of HDT toxicity.
statistical considerations
Both event free and overall survival were estimated using Kaplan-Meier methods [17]. Event free survival was calculated from the date of HDT to the time of progression of any existing disease or recurrent disease at any site, or death if this occurred without prior disease progression. Overall survival was calculated from the date of HDT to the date of last follow up or death. No statistical comparisons between groups were made due to the small patient numbers. The cut off date for the analysis was 1 February 2006.
Toxicity was graded according to the National Cancer Institute—Common Toxicity Criteria (NCI-CTC), version 2.0 [18].
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results |
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survival
Median follow up is 5.0 years from the time of HDT. Two-year and 5-year event free survival were 42.5% (95% confidence intervals (CI), 26–59%) and 38.2% (95% CI, 21–55%) respectively. As at 1 February 2006, 15 of the 33 patients were still alive, 13 in continuous complete remission, at a median follow up of 60 months in this group of patients. The estimated 2 and 5 year overall survival for the whole group was 50.7% (95% CI, 33–68%) and 42.8% (95% CI, 25–61%) respectively (Figure 1).
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The response rate, evaluable in 17 of the 19 patients not in CR at time of HDT, was 52.9 % (95% CI, 28–77%), with seven patients achieving a CR and two patients a PR. Three further patients had minor or short-lived responses, three patients had stable disease, and two patients had progressive disease.
No differences in survival according to disease status at relapse (Figure 2a), or timing of relapse (Figure 2b) were evident. Better survival was seen for those treated with busulphan and melphalan compared to other regimens, (Figure 2c). Patients treated for lung recurrence had a superior survival, with a 5-year overall survival of 63.6%, compared to 42.4% in those with local recurrence or progression, and 14.3% in those with extra-pulmonary recurrence. None of the four patients with combined local and lung recurrence survived beyond 20 months from HDT (median survival, 7 months, range 4–20).
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Grade 3 and 4 toxicities are shown in Table 2. Grade 3 or 4 infection was seen in all patients, with two patients (6%) experiencing grade 4 infection. The median number of days with an absolute neutrophil count of <0.5 x 109/l was 8.5 days (range 5–13), with a median of 6 days (range 5–13) in patients who received G-CSF, compared to 10 days (range, 8–12) in patients without G-CSF, (P = 0.001). There was no difference in the number of days requiring intravenous antibiotic support between those treated with G-CSF and those who were not (mean number of days, 10.36 versus 9.42) or the number of days with fever >38°C (mean number of days, 3.72 versus 4.37). The median number of days requiring blood and platelet transfusion support was 1 day (range 0–6) and 4.5 days (range 1–26) respectively. Veno-occlusive Disease (VOD), assessed according to Bearman [19
] was observed in five of 23 patients treated with busulphan (22%). Seizures were not observed.
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Although there were no acute toxic deaths from HDT, one patient, treated in second CR following cerebral metastatectomy for cranial metastases, died of gastrointestinal toxicity 3 months after HDT with busulphan and melphalan. A second patient treated with melphalan and TBI for lung recurrence suffered radiation pneumonitis with lung abscesses and chronic infection, dying 18 months later. Recurrent disease was suspected but not proven. One further patient died of Pneumocystis carinii during 3rd line chemotherapy for a subsequent relapse, 7 months after HDT with busulphan and melphalan.
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discussion |
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No randomised trials to determine any benefit for HDT in ESFT have been completed. This treatment is, however, widely used both as part of first line treatment [10
, 15, 20–23], and for relapsed disease [8–10, 15]. In 2002, 14% of all solid tumour HDT procedures carried out within the European Bone Marrow Transplant (EBMT) group were for ESFT, and between 1991–2002, there was a 5.9-fold increase in patients receiving HDT for this disease [24].
The 5-year survival of 43% in this study is similar to that in other smaller series of patients with relapsed ESFT treated with HDT. In a series of 24 patients treated with either melphalan, etoposide and TBI (n = 13) or tandem melphalan and etoposide (n = 11), the event free survival following HDT was 46% and 45% respectively at a median follow up of 106 months (range, 18–190) [15]. Similarly Hawkins et al. [25] reported a 5-year event free survival of 42% in 14 patients with relapsed disease treated with busulphan, melphalan, and thiotepa.
In the largest series of patients with recurrent ESFT, the 5-year survival for 123 patients registered with the EBMT was 31% for those treated with HDT at the time of second CR and 13% for patients treated with residual disease [26]. An earlier report from the same series found that favourable outcome was limited to those with localised disease at initial diagnosis, and that distant relapse had a more favourable prognosis compared to local failure [13].
A limitation of this study and others is that the patients treated with HDT invariably represent a selected cohort of patients with responsive disease. In an attempt to control for such bias, Barker et al. [9] carried out a retrospective analysis of 55 patients with recurrent ESFT, 13 of whom received HDT. Patients who received HDT were found to have a superior survival; with a 5-year overall survival of 77% compared with 7%, which remained significant even when other factors were accounted for in a multivariate analysis.
In this study the greatest benefit was observed in patients with lung metastases at recurrence. It may therefore be possible that similar results could have been achieved had lung irradiation been used instead. In a retrospective analysis which included 16 patients with isolated pulmonary recurrence, Rodriguez-Galindo et al. [6] reported superior survival in those who had received lung irradiation compared to those had not (5-year EFS, 30% versus 17%, P = 0.018). The current Euro-Ewing study is prospectively examining the role of first line consolidation treatment with HDT compared with standard chemotherapy with lung irradiation for patients with lung metastases at diagnosis.
There was no difference in survival between patients treated for early relapse (within 2 years of diagnosis) or late relapse, despite this being a prognostic factor in patients with recurrent ESFT [4, 6, 8, 9]. This may be due to small patient numbers, or to patient selection, whereby only those with good prognostic features received HDT. However, there did appear to be a trend for improved survival in patients who received busulphan and melphalan compared to non-busulphan regimens. This is in accordance with a report by the EBMT group, where patients with primary poor prognosis ESFT treated with busulphan containing regimens had a 5-year survival of 60% compared with 26% for those not treated with busulphan [26].
HDT in this group of patients has important toxicities. One patient in this series died of gastrointestinal toxicity, 3 months after HDT with busulphan and melphalan, and a second patient required continued supportive care for radiation pneumonitis as a result of TBI. Additionally, two patients experienced grade-4 infection. All other toxicities were as anticipated, but manageable.
The results of this study confirm that long-term survival can be attained in patients with recurrent or refractory ESFT. Given the potential toxicity of HDT in this setting, there remains a need for prospective randomised clinical trials in patients with recurrent disease, particularly between HDT and conventional treatment with lung irradiation in patients with disease confined to the lung at relapse. In the interim, in view of the universally poor prognosis in this group of patients, HDT would appear to be an appropriate treatment goal for patients with minimal, responsive disease following conventional second-line treatment.
Received for publication February 27, 2006. Revision received April 3, 2006. Accepted for publication April 12, 2006.
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References |
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1. Ahrens S, Hoffmann C, Jabar S et al. Evaluation of prognostic factors in a tumor volume-adapted treatment strategy for localized Ewing sarcoma of bone: the CESS 86 experience. Cooperative Ewing Sarcoma Study. Med Pediatr Oncol 1999; 32: 186–195.[CrossRef][ISI][Medline]
2. Paulussen M, Ahrens S, Dunst J et al. Localized Ewing tumor of bone: final results of the cooperative Ewing's Sarcoma Study CESS 86. J Clin Oncol 2001; 19: 1818–1829.
3. Jurgens H, Exner U, Gadner H et al. Multidisciplinary treatment of primary Ewing's sarcoma of bone. A 6-year experience of a European Cooperative Trial. Cancer 1988; 61: 23–32.[CrossRef][ISI][Medline]
4. Cotterill SJ, Ahrens S, Paulussen M et al. Prognostic factors in Ewing's tumor of bone: analysis of 975 patients from the European Intergroup Cooperative Ewing's Sarcoma Study Group. J Clin Oncol 2000; 18: 3108–3114.
5. ISRCTN Register. Database of randomised controlled trials with an International Standard Randomised Controlled Trial Number (ISRCTN), http://controlled-trials.com/isrctn/trial/l/0/61438620.html. Date accessed: 13.02.2006.
6. Rodriguez-Galindo C, Billups CA, Kun LE et al. Survival after recurrence of Ewing tumors: the St Jude Children's Research Hospital experience, 1979–1999. Cancer 2002; 94: 561–569.[CrossRef][ISI][Medline]
7. Shankar AG, Ashley S, Craft AW, Pinkerton CR. Outcome after relapse in an unselected cohort of children and adolescents with Ewing sarcoma. Med Pediatr Oncol 2003; 40: 141–147.[CrossRef][ISI][Medline]
8. Bacci G, Ferrari S, Longhi A et al. Therapy and survival after recurrence of Ewing's tumors: the Rizzoli experience in 195 patients treated with adjuvant and neoadjuvant chemotherapy from 1979 to 1997. Ann Oncol 2003; 14: 1654–1659.
9. Barker LM, Pendergrass TM, Sanders JE, Hawkins DS. Survival After Recurrence of Ewing's Sarcoma Family of Tumors. J Clin Oncol 2005; 23: 4354–4362.
10. Ladenstein R, Gadner H, Hartmann O et al. The European experience with megadose therapy and autologous bone marrow transplantation in solid tumors with poor prognosis (Ewing sarcoma, germ cell tumors and brain tumors). Wien Med Wochenschr 1995; 145: 55–57.[Medline]
11. Burdach S, van Kaick B, Laws HJ et al. Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Dusseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria. Ann Oncol 2000; 11: 1451–1462.
12. Frohlich B, Ahrens S, Burdach S et al. High-dosage chemotherapy in primary metastasized and relapsed Ewing's sarcoma. (EI)CESS. Klin Padiatr 1999; 211: 284–290.[ISI][Medline]
13. Ladenstein R, Lasset C, Pinkerton R et al. Impact of megatherapy in children with high-risk Ewing's tumours in complete remission: a report from the EBMT Solid Tumour Registry. Bone Marrow Transplant 1995; 15: 697–705.[ISI][Medline]
14. Whelan JS, McTiernan A, Kakouri E, Kilby A. Carboplatin-based chemotherapy for refractory and recurrent Ewing's tumours. Pediatr Blood Cancer 2004; 43: 237–242.[CrossRef][ISI][Medline]
15. Burdach S, Meyer-Bahlburg A, Laws HJ et al. High-dose therapy for patients with primary multifocal and early relapsed Ewing's tumors: results of two consecutive regimens assessing the role of total-body irradiation. J Clin Oncol 2003; 21: 3072–3078.
16. Valteau-Couanet D, Oberlin O, Michon J et al. Treatment of metastatic Ewing's sarcomas with a strategy based on busulfan and melphalan high dose chemotherapy consolidation after conventional chemotherapy – a study of the French Society of Pediatric Oncology (SFOP). Acta Orthop Scand 1997; 68 (Suppl 277): S68 (abstr 27).
17. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457–481.[CrossRef][ISI]
18. Cancer Therapy Evaluation Program. Common Toxicity Criteria, Version 2.0. DCTD, NCI, NIH, DHHS March, 1998.
19. Bearman SI. The syndrome of hepatic veno-occlusive disease after marrow transplantation. Blood 1995; 85: 3005–3020.
20. Paulussen M, Ahrens S, Burdach S et al. Primary metastatic (stage IV) Ewing tumor: survival analysis of 171 patients from the EICESS studies. European Intergroup Cooperative Ewing Sarcoma Studies. Ann Oncol 1998; 9: 275–281.
21. Horowitz ME, Kinsella TJ, Wexler LH et al. Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing's sarcoma and rhabdomyosarcoma. J Clin Oncol 1993; 11: 1911–1918.
22. Meyers PA, Krailo MD, Ladanyi M et al. High-dose melphalan, etoposide, total-body irradiation, and autologous stem-cell reconstitution as consolidation therapy for high-risk Ewing's sarcoma does not improve prognosis. J Clin Oncol 2001; 19: 2812–2820.
23. Prete A, Rondelli R, Dallorso S et al. Long-term overall survival and event free survival after high-dose chemotherapy and stem cell support in poor-prognosis Ewing's sarcoma of childhood. Bone Marrow Transplant 2005; 35 (suppl 2): S52 (abstract).
24. Gratwohl A, Baldomero H, Demirer T et al. Hematopoetic stem cell transplantation for solid tumors in Europe. Ann Oncol 2004; 15: 653–660.
25. Hawkins D, Barnett T, Bensinger W et al. Busulfan, melphalan, and thiotepa with or without total marrow irradiation with hematopoietic stem cell rescue for poor-risk Ewing-Sarcoma-Family tumors. Med Pediatr Oncol 2000; 34: 328–337.[CrossRef][ISI][Medline]
26. Ladenstein R, Hartmann O, Pinkerton CR et al. A multivariate and matched pair analysis of high-risk Ewing tumor (ET) patients treated by megatherapy (MGT) and stem cell reinfusion (SCR) in Europe. Proc Am Soc Clin Oncol 1999; 18: 555 (abstract).
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