Cochrane Database of Systematic Reviews

High-dose chemotherapy for children and young adults with

stage IV rhabdomyosarcoma (Review)

Admiraal R, van der Paardt M, Kobes J, Kremer LCM, Bisogno G, Merks JHM

Admiraal R, van der Paardt M, Kobes J, Kremer LCM, Bisogno G, Merks JHM.
High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma.
Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD006669.
DOI: 10.1002/14651858.CD006669.pub2.

www.cochranelibrary.com

High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

High-dose chemotherapy for children and young adults with

stage IV rhabdomyosarcoma

Rick Admiraal2 , Marcel van der Paardt3 , Jasmijn Kobes4 , Leontien CM Kremer1 , Gianni Bisogno5 , Johannes HM Merks1

1 Paediatric Oncology, Emma Children’s Hospital

/ Academic Medical Center, Amsterdam, Netherlands. 2 Paediatrics, Emma Children’s
Hospital / Academic Medical Center, Amsterdam, Netherlands. 3 Academic Medical Center, Amsterdam, Netherlands. 4 Child Health
Care, GGD Gooi & Vechtstreek, Hilversum, Netherlands. 5 Paediatrics, University Hospital of Padova, Padova, Italy

Contact address: Johannes HM Merks, Paediatric Oncology, Emma Children’s Hospital / Academic Medical Center, PO Box 22660,
Amsterdam, 1100 DD, Netherlands. j.h.merks@amc.uva.nl.

Editorial group: Cochrane Childhood Cancer Group.

Publication status and date: New, published in Issue 12, 2010.
Review content assessed as up-to-date: 21 September 2009.

Citation: Admiraal R, van der Paardt M, Kobes J, Kremer LCM, Bisogno G, Merks JHM. High-dose chemotherapy for children and
young adults with stage IV rhabdomyosarcoma. Cochrane Database of Systematic Reviews 2010, Issue 12. Art. No.: CD006669. DOI:
10.1002/14651858.CD006669.pub2.

Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Prognosis for patients with metastatic disease has not
improved significantly in the past decades. High-dose chemotherapy (HDC) seems to be an attractive option to treat minimal residual
disease in metastatic rhabdomyosarcoma patients.

Objectives

The objective of the review was to assess the effectiveness of HDC with stem cell rescue (SRC) versus standard-dose chemotherapy in
improving event-free survival (EFS) and overall survival (OS) of children and young adults with metastatic rhabdomyosarcoma.

Search methods

We searched the databases of MEDLINE (1966 to December 2009), EMBASE (1980 to December 2009) and CENTRAL (The
Cochrane Library Issue 1, 2009). In addition, we handsearched the reference lists of selected papers and conference proceedings of the
SIOP, ASPHO and ASCO meetings (all 2000 to 2009).

Selection criteria

Randomised controlled trials (RCT), prospective or historical controlled clinical trials (CCT), in which HDC with SCR was com-
pared to conventional chemotherapy and prospective case series (non-controlled clinical trials) including at least 20 naive metastatic
rhabdomyosarcoma patients

Data collection and analysis

Two review authors independently performed the study selection, quality assessment and data extraction.
High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results
No RCTs could be identified. We identified one prospective CCT, one retrospective CCT and one non-controlled clinical trial. Another
CCT has been published as an abstract. All studies have severe methodological limitations, in particular selection bias could not be
excluded. One CCT reported a significantly worse OS compared to oral maintenance therapy, however in a subgroup of high-risk patients
no difference could be found. The retrospective CCT reported a similar survival for HDC compared to conventional chemotherapy.
The non-controlled clinical trial and the CCT reported as a conference proceeding reported survival outcomes comparable to previous
studies. Data on toxicity showed more grade 3-4 toxicity in the HDC group. However, there was no difference in the number of toxic
deaths.
Authors’ conclusions
Overall, the results of this review do not justify the use of HDC with SCR as a standard therapy for children with metastatic
rhabdomyosarcoma. However, all reported studies were possibly subject to significant bias, especially selection bias. This might have
underestimated the measured effect of HDC. As a result, a clinically important excess of adverse risk patients in the HDC arms may
explain the non-beneficial effect of HDC. Only a large prospective RCT will be able to answer the question of whether HDC with
SCR adds to survival or not definitively.

PLAIN LANGUAGE SUMMARY

High-dose chemotherapy for children and young adults with metastatic rhabdomyosarcoma
Rhabdomyosarcoma is the most common soft tissue sarcoma of childhood. Fifteen percent of rhabdomyosarcoma patients already
have metastases when the disease is discovered. With conventional dose chemotherapy survival generally is poor, therefore using ’high-
dose’ chemotherapy has been studied to see if this can improve survival. This type of chemotherapy has been shown to improve survival
in metastatic neuroblastoma, another type of childhood cancer, when given after conventional chemotherapy with only very small
amounts of neuroblastoma left. This might also be true for metastatic rhabdomyosarcoma. An alternative way of using high-dose
chemotherapy is to use it ’up front’, at the start of treatment; applied this way it could potentially kill tumour cells before resistance to
chemotherapy develops.
Besides creating a possible benefit for patients, high-dose chemotherapy introduces significant extra risk of side effects above those of
conventional chemotherapy. These include mucositis (severe inflammation of the mouth and gut) and bone marrow aplasia (when the
body cannot make any blood elements and is at risk of life-threatening bleeding and infection). The administration of cells which can
restore the bone marrow (haemopoietic stem cells) reduces this risk. These stem cells come from the patient themselves (autologous)
or are donated from volunteers (allogenic). During the first weeks after high-dose chemotherapy, infections, bleeding and metabolic
problems may occur, possibly counteracting the potential benefit of improved tumour control. In this review the authors analysed all
relevant studies on the use of high-dose chemotherapy in metastatic rhabdomyosarcoma patients. The authors of this review found no
evidence that supported the use of high-dose chemotherapy as a standard therapy for metastatic rhabdomyosarcoma.

High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma (Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.