High-Dose Busulphan/Melphalan with Autologous Stem Cell Rescue in Ewing’S Sarcoma

High-dose busulphan/melphalan with autologous stem cell rescue in Ewing’s sarcoma

A Atra1, JS Whelan,2 V Calvagna1, AG Shankar1, S Ashley1, V Shepherd1, RL Souhami2 and CR Pinkerton1

1Department of Paediatric Oncology, The Royal Marsden NHS Trust, Sutton; and 2The Meyerstein Institute of Oncology, The Middlesex Hospital, London, UK

Summary: Patients and methods

Eighteen patients with poor risk Ewing’s sarcoma Eighteen patients were entered into the study. There were (including 11 patients with metastatic disease at nine females. The median age at diagnosis was 14.2 years presentation) received consolidation therapy of busul- (range 2.75–30 years). Primary tumours were of the central phan and melphalan with autologous stem cell rescue. skeleton in 10 cases and long bones in eight cases. Eleven There were nine females. The median age at diagnosis cases were metastatic at initial presentation, 10 with pul- was 14.2 years (range 2.75–30 years). There was one monary disease and one with bone marrow involvement. early death due to cytomegalovirus pneumonitis. One The primary tumour of the metastatic cases was central patient developed a single generalised convulsion during skeleton in six, and long bones in five cases. Six of the busulphan therapy. Severe renal toxicity was not seven non-metastatic patients had bulky primary tumours encountered. One patient developed veno-occlusive dis- (у100 ml) and the seventh patient was in second complete ease of the liver (VOD) which eventually resolved. With remission at the time of high-dose therapy. In total 12 a median follow up of 2 years, 13 patients survive patients were in first complete remission (CR1), four in including six with initial metastatic disease. We con- CR2, one in partial remission (PR) and one with progress- clude that high-dose busulphan/melphalan is well-toler- ive disease (PD) at the time of HDT. The characteristics of ated and should be evaluated for efficacy in a larger these patients including their initial chemotherapy are series of patients with high risk Ewing’s sarcoma. shown in Table 1. Keywords: busulphan/melphalan; high-risk Ewing’s Pretreatment investigations besides clinical evaluation sarcoma; autologous stem cell rescue included radiological assessment (CT scan and/or MRI) of all measurable disease, haematological and biochemical parameters, bone marrow aspirate/trephine and assessment of renal function including glomerular filtration rate. Daily The introduction of combined modality treatment has led measurement of haematological and biochemical para- to a rapid improvement in the prognosis for many patients meters were done from day 1 post-stem cell re-infusion 1–3 with Ewing’s sarcoma. However, the results from indi- until recovery. Informed verbal consent regarding the use vidual centres and cooperative groups have consistently of the drug combination and stem cell harvest procedure identified the inferior prognosis of patients with large vol- was obtained from the parents, or patients, of all cases ume primary tumours and/or metastatic disease.4,5 entered into the study. High-dose chemotherapy with autologous stem cell rescue (bone marrow and more recently peripheral blood stem cell (PBSC)) is under evaluation in the management of Treatment 6–9 many cancers, particularly haematological malignancies. All patients were treated with busulphan 16 mg/kg (14 Ewing’s sarcoma may be a suitable disease for this strategy patients) or 600 mg/m2 (four patients), orally over 4 days because of its sensitivity to alkylating agents. Several small in 6 hourly divided doses, after 12 h prehydration, from studies have suggested that some patients with poor risk day −5to−2 prior to stem cell re-infusion. This was fol- 10–13 Ewing’s sarcoma may benefit from high-dose therapy. lowed by the intravenous infusion of melphalan at a dose The combination of busulphan/melphalan has been used in of 160 mg/m2 (11 patients) or 140 mg/m2 (six patients) on patients with acute or chronic myeloid leukaemia and other day −1. Cryopreserved autologous stem cells, bone marrow 14–16 solid tumours. This report describes the combined (BM) (seven patients), peripheral blood stem cells (PBSC) experience of two centres using a single regimen, busul- (seven patients) or both (four patients), were infused on the phan and melphalan followed by autologous stem cell following day (DO), at least 48 h after completion of the rescue in patients with Ewing’s sarcoma. busulphan course (Table 2). PBSC were harvested without the use of growth factors Correspondence: Dr A Atra, Department of Paediatric Oncology, The in 11 patients and cyclophosphamide and G-CSF priming Royal Marsden NHS Trust, Downs Road, Sutton, Surrey, SM2 5PT in seven patients. PBSC harvests were timed after chemo- Received 22 March 1997; accepted 26 June 1997 therapy for maximum yield (in non-primed patients) and Busulphan/melphalan in Ewing’s sarcoma A Atra et al 844 Table 1 Details of patients and prior treatment Table 2 Type and dose of stem cell rescue

Sex Age Site Previous treatment Stem cell MNC 108/kg CFU-GM 104/kg Time of HDT (year) BM 3.09 8.4 CR1 F 15 L iliac bone IVAD × 4; surgery; DXT; BM 2.24 NK CR1 VP/Ifos × 2 BM 2.73 10.6 CR1 + F 16 R iliac bone IVAD × 4; surgery; VP/Ifos BM PBSC 3.06 15.43 CR1 × 2 BM 1.26 17.02 CR1 BM 4.66 36.9 CR1 × M 12 R tibia IVAD 4; surgery; VP/Ifos BM + PBSC 2.65 17.4 CR1 × × 3, IVA 2 BM + PBSC 6.05 7.54 CR1 F 8 R femur IVAD × 4; surgery; VP/Ifos BM 1.6 12.9 CR1 × 3BM+PBSC 5.49 3.08 CR1 M 12.15 L iliac bone, IVAD × 4; surgery; VP/Ifos BM 1.64 10.63 CR1 Scapula and bone × 2; DXT PBSC 4 40.5 CR1 marrow PBSC 3.8 26.9 CR2 PBSC 1.4 28.1 CR2 × × M 16.5 Second and ﬁfth IVAD 4; VP/Ifos 2 PBSC 6.0 NK PR1 metatarsals and No surgery or DXT PBSC 5.4 59.1 PD lungs PBSC 5.6 66.7 CR2 M 9.75 R pubic bone IVAD × 4; surgery; VP/Ifos PBSC NK NK CR2 R lung × 3 M 13.6 Pubic bones IVAD × 4, IVA × 2; DXT; NK = not known; PD = progressive disease. Lungs VP/Ifos × 2, VAC × 2 F 2.75 Cervical (C3) IVAD × 6; VP/Ifos × 2 vertebra No surgery or DXT patients who remain in complete remission, including six F 17.3 Iliac bones, skull, IVAD × 4; VP/Ifos × 3; with metastatic disease (ﬁve lungs and one bone marrow) sacrum and lungs CYVAD × 3 at diagnosis (Figure 1). No surgery or DXT Five patients relapsed after high-dose therapy (two pul- M 13 L iliac bone IVAD × 4; DXT, IVA × 2; × monary, two in other bones and one in bone marrow). All VP/Ifos 2 have died except one patient who relapsed in the lung × M 30 R thigh & lungs EVAIA 8; surgery (single lesion) 7 months after busulphan/melphalan. He sur- + + + F 25 R scapula and Epi VCR Cyclo DTIC vived following lobectomy and unilateral whole lung radio- lungs × 3; DXT; EVAIA × 8 therapy and is alive in complete remission 18 months post- F 18 R femur, R lung VAIA × 4; surgery; DXT; pleura EVAIA × 3 high-dose therapy. Neutrophil Ͼ0.5 × 109/l occurred at a median of 12 days M 12 R humerus and EVAIA × 8; CbEC × 2; lungs DXT (range, 10–24 days) with a slower platelet recovery Ͼ50 × 109/l ranging from 24–52 days post-stem cell rescue. M 14 R pelvis and lung EVAIA × 8; CbEC × 2; DXT One patient experienced a single grand mal convulsion last- F 14 L femur and IVAD × 4; CbEC × 4; DXT ing 5 min during busulphan despite prophylactic phenytoin lungs measured at therapeutic levels, with no sequelae. There was F 9 R femur IVAD × 4; surgery; CbE × one toxic death, at day 51 due to pulmonary haemorrhage 4; DXT secondary to cytomegalovirus infection. Mucositis (WHO grade IV) and diarrhoea (WHO grade II–IV) requiring anal- IVAD = ifosfamide, vincristine, adriamycin; VP/Ifos = gesia were documented, and total parenteral nutrition was etoposide/ifosfamide; IVA = ifosfamide, vincristine, actinomycin; VAC = required in all patients. All patients required at least one vincristine, actinomycin, cyclophosphamide; CYVAD = cyclophosphamide, vincristine, adriamycin; EVAIA = etoposide, vincristine, actinomycin/adriamycin, ifosfamide; DTIC = dacarbazine; CbEC = car- boplatin and etoposide, cyclophosphamide; DXT = local irradiation. 100

usually performed on two separate occasions to maximise 80 mononuclear cell counts. Phenytoin at a dose 8 mg/kg/day orally in two divided 60 doses was commenced 2 weeks prior to busulphan as prophylaxis against neurotoxicity and continued until 48 h 40 after the last dose of busulphan. No prophylactic antibiotics were used. Only one patient received G-CSF (5 ␮g/kg/day) + 20 post-stem cell rescue from day 10. % Probability of survival

0 Results 012345678

With a median follow-up of 2 years, (range 2 months–7 Years since bone marrow transplant years) after high-dose therapy there are 13 surviving Figure 1 Survival after bone marrow transplant. Busulphan/melphalan in Ewing’s sarcoma A Atra et al 845 course of systemic antibiotics for episodes of febrile neutro- etoposide with encouraging results as compared to histori- penia with addition of systemic antifungal agents in the cal control groups.18,19 majority of patients. One patient developed clinical and bio- Other nonrandomised studies using high-dose alkylating chemical features of VOD which resolved. Another patient agents ± TBI failed to demonstrate any benefit in poor risk developed haemorrhagic cystitis which continues to recur patients.20 The combination of busulphan/melphalan has but which required no intervention. been used in patients with myeloid malignancies and other solid tumours with acceptable toxicity and anti-tumour activity.14–16 Analysis of the European Bone Marrow Trans- Discussion plant registry (EBMT) data showed that consolidation of remission with busulphan/melphalan and autologous stem The definition of high risk Ewing’s sarcoma varies between cell rescue in children with high-risk Ewing’s sarcoma who study groups. In general, those with bulky primary tumours were treated with a wide range of initial chemotherapy lead (у100 ml tumour volume) do poorly and those with bone to a 5-year EFS of 51% with acceptable toxicity.19 The marrow or bone involvement are unlikely to be cured with avoidance of TBI should help to reduce the long-term side- conventional therapy. The UKCCSG experience indicates effects particularly the effect on growth and endocrine that only 10–20% with lung metastases at diagnosis survive functions. long term and those with bone metastases were all dead In the present study, busulphan was given in divided at 30 months from diagnosis.5 In some studies the use of doses over 4 days, a schedule based on experience in leu- ifosfamide to replace cyclophoshamide has been associated kaemia. Phenytoin was used as an anticonvulsant during with an increase in overall survival and EFS but with busulphan therapy to prevent neurological toxicity. It has, increased morbidity, mainly tubular nephropathy.5,17 however, been found that phenytoin may enhance the The German (CESS 81) study confirmed the adverse metabolism of busulphan and we have recently changed to prognostic significance of bulky tumours (у100 ml) and the use of clonazepam to avoid this complication.21 poor response to chemotherapy (more than 10% viable The kinetics of high-dose busulphan have now been tumour in the resected specimens) with DFS at 3 years of widely studied in children. The short half-life of the drug 31% compared to 79% for patients with small tumours or in children, due to its rapid clearance, leads to a lower area with less than 10% viable tumours in the resected tumour.1 under the concentration curve (AUC) than in adults. Conse- In the follow-up study (CESS 86) ifosfamide replaced quently, when based on weight alone a relatively lower cyclophosphamide and local therapy (surgery ± AUC is achieved.22–24 This may not only explain the lower radiotherapy) was brought forward to week 9. Also, incidence of neurological toxicity in small children than in patients were randomised to conventional or hyperfraction- adults but could lead to a lower therapeutic effect. A dose ated radiotherapy with four-drug chemotherapy continued based on surface area has therefore been developed and throughout. EFS for patients with tumours у100 ml shown to produce more consistent AUC levels.22,23 This increased from 32 to 66% with no difference between the strategy leads to increased toxicity but improved efficacy two RT arms in terms of survival or toxicity. It was con- has not yet been demonstrated. cluded that patients with larger tumours may benefit from In the present study drugs were well tolerated. Toxicity intensified chemotherapy. was acceptable, with only one procedure-related mortality High-dose chemotherapy with or without radiotherapy (5.5%) and no significant renal or (fatal) hepatic toxicity. and autologous stem cell rescue is being increasingly used Thirteen patients remain in complete remission including in many childhood cancers. Several small studies have sug- six with metastatic disease at presentation (Figure 1). The gested that some patients with poor risk Ewing’s sarcoma median survival of metastatic patients is 3 years and 9 may benefit from this modality.10–13 Most published data months from the time of megatherapy with a median involve TBI-based regimens using melphalan/TBI/ progression-free survival of 1 year 5 months (Figure 2). Compared to historical controls, these data show promis- ing disease control rates. The role of HDC in Ewing’s sarcoma merits evaluation in an unselected group of clearly 100 defined poor risk patients, possibly with a randomised ques- tion regarding the value of TBI in the treatment regimen. 80 Such a study would require international collaboration.

60 Acknowledgement

40 We would like to thank Jane Neil for her secretarial support.

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