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.
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.
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).
Randomised controlled trials (RCT), prospective or historical controlled clinical trials (CCT), in which HDC with SCR was compared 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.
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.
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.