Pediatr Blood Cancer 2009;53:238

LETTER TO THE EDITORLow Dose Cytarabine in Patients With Relapsed or Refractory Ewing Sarcoma

To the Editor: We read with great interest the article from Dubois

reporting the use of intermediate dose of cytarabine in patients with

relapsed or refractory Ewing sarcoma (ES) [1]. Indeed, upon the

publication of Stegmaier et al., [2] as well as based on previous data

[3], we decided to propose cytarabine to patients with relapsing and

refractory ES and positive EWS/FLI translocation in a palliative

setting. To bring new data on the use of cytarabine in children with

ES, we report here our experience.

Three patients were treated (two males and one female), age of

13, 17 and 15 years old, respectively, with localized (patients 1

and 2) or metastatic (patient 3) disease at diagnosis. The primary site

of the disease was respectively: iliac bone, radius and talus,

respectively. The patients were initially treated according to the

EuroEwing99 protocol [4]. Patient 3 underwent high-dose chemo-

therapy as part of the first line treatment. Local therapy consisted of

surgery for patients 1 and 2 and radiotherapy for patient 3. All three

patients were in CR after the completion of the first line treatment.

They all presented with a metastatic relapse and received two to six

additional types of treatment before initiation of cytarabine. Patient

2 received high-dose chemotherapy as part as the second line

treatment.

To reach the concentrations of cytarabine used in the in vitro

experiments reported by Stegmaier et al. [1] while attempting to

avoid toxicities in this palliative context, cytarabine was given at the

dose of 100 mg/m2/day for 5 days every 2 weeks. Patient 1 received

three courses and despite a transient clinical improvement (decrease

in fever and in antalgic doses) after the first course, the disease

progressed and cytarabine treatment was stopped after the third

cycle. Patients 2 and 3 received two courses but disease progression

was observed. There was no grade III–IV toxicity except for patient

3, who required several platelets transfusions. Nevertheless, for this

patient, platelets transfusions were necessary before initiation of the

treatment with cytarabine.

Given the number of patients reported here, we cannot conclude

that cytarabine given with this schedule is or is not efficacious in

children with refractory or relapsing ES. Alternatively, cytarabine

could also be given on a different schedule, possibly metronomi-

cally [5] or even at higher dose [6]. Lastly, cytarabine may be

combined with other anticancer agents or other FLI/EWS

modulators such as rapamycin or anti-IGF-R [7]. Based on these

preliminary results, however, we stopped studying this treatment.

Nevertheless, additional testing of cytarabine using different

schedules of administration in less heavily treated patients may be

useful. In addition, further xenograft data may be helpful in further

evaluating the use of this agent in patients with ES [2,8].

Nicolas Andre, MD, PhD*

Arnauld Verschuur, MD, PhD

Angelique Rome, MD

Carole Coze, MD, PhD

Jean-Claude Gentet, MD

Service d’Oncologie Pediatrique

Hopital pour Enfants de ‘‘la Timone’’, AP-HM

Marseille, France

Laetitia Padovani, MD

Service de Radiotherapie

hopital de ‘‘La Timone’’, AP-HM

Marseille, France

REFERENCES

1. DuBois SG, Krailo MD, Lessnick SL, et al. Phase II study

of intermediate-dose cytarabine in patients with relapsed or

refractory Ewing sarcoma: A report from the Children’s Oncology

Group. Pediatr Blood Cancer 2009;52:324–327.

2. Stegmaier K, Wong JS, Ross KN, et al. Signature-based

small molecule screening identifies cytosine arabinoside as

an EWS/FLI modulator in Ewing sarcoma. PLoS Med 2007;4:

e122.

3. Hofbauer S, Hamilton G, Theyer G, et al. Insulin-like growth factor-

I-dependent growth and in vitro chemosensitivity of Ewing’s

sarcoma and peripheral primitive neuroectodermal tumour cell lines.

Eur J Cancer 1993;29A:241–245.

4. Juergens C, Weston C, Lewis I, et al. Safety assessment of

intensive induction with vincristine, ifosfamide, doxorubicin,

and etoposide (VIDE) in the treatment of Ewing tumors in the

EURO-E.W.I.N.G. 99 clinical trial. Pediatr Blood Cancer 2006;

47:22–29.

5. Andre N, Pasquier E, Verschuur A, et al. Metronomic chemo-

therapy in paediatric oncology: Hype or Hope? Arch Pediatr in press.

6. Tomizawa D, Tabuchi K, Kinoshita A, et al. Repetitive cycles of

high-dose cytarabine are effective for childhood acute myeloid

leukemia: Long-term outcome of the children with AML treated on

two consecutive trials of Tokyo Children’s Cancer Study Group.

Pediatr Blood Cancer 2007;49:127–132.

7. Seddon BM, Whelan JS. Emerging chemotherapeutic strategies and

the role of treatment stratification in Ewing sarcoma. Paediatr Drugs

2008;10:93–105.

8. Houghton PJ. How do we Identify Novel Treatment for Childhood

Cancer? Pediatr Blood Cancer 2009;52:310–311.

� 2009 Wiley-Liss, Inc.DOI 10.1002/pbc.21940Published online 13 April 2009 in Wiley InterScience(www.interscience.wiley.com)

——————*Correspondence to: Nicolas Andre, Oncologie Pediatrique, Hopital

pour Enfants de ‘‘la Timone’’, AP-HM, 13385 Marseille Cedex 05,

France. E-mail: nicolas.andre@ap-hm.fr

Received 11 December 2008; Accepted 17 December 2008