Hematopoietic Stem-Cell Transplantation HSCT in Rhabdomyosarcoma (RMS)

What is Rhabdomyosarcoma ?

Rhabdomyosarcoma (RMS), the most common soft tissue sarcoma of childhood, shows skeletal muscle differentiation. The most common primary sites are the head and neck (e.g., parameningeal, orbital, pharyngeal), genitourinary tract, and extremities.[8] Most children with RMS present with localized disease, and with conventional multimodal therapy, the cure rate in this group is 70%–80%.[9] However, approximately 15% of children present with metastatic disease, and despite the introduction of new drugs and intensified treatment, the 5-year survival is 20%–30% for this “high-risk” group

Hematopoietic Stem-Cell Transplantation HSCT in Rhabdomyosarcoma (RMS) – Systematic Reviews

Available evidence on the use of HSCT in RMS consists of several systematic reviews summarizing a body of nonrandomized trials.

Systematic Reviews

• A 2010 Cochrane review assessed 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.[36] The review concludes that use of HDC with SCR as a standard therapy for children with metastatic rhabdomyosarcoma is not justified at this time. Overall, the quality and quantity of evidence is limited as no RCTs could be identified, and available non-randomized studies have significant methodological limitations, especially selection bias. The review states that only large, prospective RCTs could answer whether HDC with SCR improves survival in rhabdomyosarcoma.

• The AHRQ comparative effectiveness review addressed above also considered the use of HSCT in RMS.[21] The following conclusions were offered:

o Moderate-strength evidence on overall survival suggests no benefit with single HSCT compared to conventional therapy for the treatment of high-risk metastatic rhabdomyosarcoma.

o The body of evidence on overall survival with single HSCT compared to conventional therapy for the treatment of high-risk rhabdomyosarcoma of mixed tumor type is insufficient to draw conclusions.

o The body of evidence on overall survival with single HSCT compared to conventional therapy for the treatment of congenital alveolar rhabdomyosarcoma, cranial parameningeal rhabdomyosarcoma with metastasis, or the use of allogeneic transplantation for metastatic rhabdomyosarcoma was insufficient to draw conclusions.

• Weigel and colleagues published a systematic review on 2001 on the role of autologous HSCT in the treatment of metastatic or recurrent rhabdomyosarcoma, which involved a total of 389 patients from 22 studies.[37] Based on all of the data analyzing EFS and OS, they concluded that there was no significant advantage to undergoing this type of treatment.

Nonrandomized Trials

Autologous HSCT has been evaluated in a limited number of patients with “high-risk” RMS (stage 4 or relapsed) in whom CR is achieved after standard induction therapy. Data are relatively scarce, due in part to the rarity of the condition.

• Carli and colleagues[38] conducted a prospective nonrandomized study of 52 patients with metastatic RMS, who were in complete remission after induction therapy and subsequently received HDC (“megatherapy”) and autologous HSCT and compared them to 44 patients who were in remission after induction therapy who subsequently received conventional chemotherapy. No significant differences existed between the two study groups (i.e., no differences in clinical characteristics, induction chemotherapy received, sites of primary tumor, histologic subtype, age, or presence/extent 12 – TRA45.37

of metastases). Three-year EFS and OS were 29.7% and 40%, respectively, for the autologous HSCT group and 19.2% and 27.7%, respectively, for the group that received standard consolidation chemotherapy. The difference was not statistically significant (p=0.3 and 0.2 for EFS and OS, respectively). The median time after chemotherapy to relapse was 168 days for the autologous HSCT group, and 104 days for the standard chemotherapy group (p=0.05). Therefore, although there was some delay to relapse, there was no clear survival benefit from using autologous HSCT compared to conventional chemotherapy.

• Klingebiel and colleagues prospectively compared the efficacy of two HDC treatments followed by autologous stem-cell rescue versus an oral maintenance treatment (OMT) in 96 children with stage IV soft tissue sarcoma (88 of whom had rhabdomyosarcoma).[39] Five-year OS probability for the whole group was 0.52 + 0.14 for the patients who received OMT (n=51) and 0.27 + 0.13 for the transplant group (n=45; p=0.03). For the patients with rhabdomyosarcoma, 5-year OS probability was 0.52 + 0.16 with OMT versus 0.15 + 0.12 with transplant (p=0.001). The authors concluded that transplant has failed to improve prognosis in metastatic soft tissue sarcoma, but that OMT could be a promising alternative.

• McDowell and colleagues reported the results of the International Society of Paediatric Oncology (SIOP) study MMT-98, for pediatric patients from 48 centers with metastatic rhabdomyosarcoma, entered into the study from 1998 to 2005.[40] There were a total of 146 patients entered, aged 6 months to 18 years. The patients were risk-stratified and treated accordingly. One hundred and one patients were considered poor risk patients (PRG) if they were older than 10 years of age, or had bone marrow or bone metastases. Planned therapy for the PRG was induction therapy, sequential high-dose chemotherapy and peripheral blood autologous HSCT and finally, maintenance therapy. Seventy-nine of the 101 PRG patients (78.2%) underwent the high-dose therapy, after which 67.1% achieved a partial or complete response. Sixty-seven of the 101 PRG patients received local treatment: 37 radiation alone, 10 surgery alone and 20 both modalities. No treatment-related deaths were reported in the PRG. Three- and 5-year EFS for the PRG group was 16.5% and 14.9%, respectively and 3 and 5-year OS were 23.7% and 17.9%, respectively [HR=2.46; CI: 1.51-4.03; p<0.001).

The most recently published evidence on the use of HSCT for treatment of RMS is not suggestive of treatment benefit.

Clinical Practice Guidelines

No evidence-based clinical practice guidelines were identified on the use of autologous or allogeneic HSCT in the treatment of RMS.