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Does high-dose chemotherapy have an impact on outcome of rhabdomyosarcoma compared to standard chemotherapy?
- Population: Rhabdomyosarcoma
- Intervention: high-dose/myeloablative chemotherapy with autologous stem cell rescue
- Comparison: standard chemotherapy
- Outcomes: overall survival, event-free survival, toxicity
Authors: Ashika Ramamurthy, Natacha Omer, Julie Cayrol, Elizabeth Connelly, Jeremy Lewin, Vivek Bhadri, Joanna Connor, Peter Grimison, Angela Hong and the ANZSA Sarcoma Guidelines Working Party
Rhabdomyosarcoma (RMS) describes a subset of small blue round cell tumours derived from primitive mesenchymal cells that have retained their capacity for skeletal muscle differentiation (1-3). RMS most commonly occur between the age of 1 and 5 years old though also occur in older children and adults. RMS frequently arise in the head and neck and urogenital regions though can arise anywhere in the body. RMS is subcategorised by histological subtypes and the presence of the FOXO1-PAX3/7 gene fusion. The fifth edition of WHO Classification of Tumours of Soft tissue and Bone (2020) recognises four major histological subtypes; alveolar, embryonal, pleomorphic and spindle cell / sclerosing RMS (1). Embryonal RMS (ERMS) and alveolar RMS (ARMS), which are predominantly seen in children, are the most common RMS subtypes. FOXO1-PAX3/7 gene fusion positivity, which confers a poorer prognosis, is frequently found in ARMS (80-90%) and distinguishes ARMS from ERMS. ERMS is associated with a more favourable prognosis (4).
RMS are considered highly sensitive to chemo- and radiotherapy. Multi-agent chemotherapy has led to significant improvement in survival rates in localised RMS. Survival rates in metastatic and relapsed RMS however, remain low, below 30% (5). High-dose chemotherapy (HDT) with autologous stem cell transplant (ASCT) has been postulated as an alternative to further conventional chemotherapy, or to consolidate primary treatment, to improve outcomes in RMS patients with unfavourable characteristics. The rationale for HDT is to exploit the dose-response relationship with chemotherapy agents, where relatively small changes in dose may impact tumour cell kill in these highly chemo-sensitive tumours. Myelosuppression is a dose-limiting toxicity of these agents; however this can be overcome when treatment is supported by autologous stem cell rescue, enabling HDT use (6). The relative benefit of HDT, however, remains uncertain and must be considered against severe haematological and non-haematological toxicities, including death, associated with treatment.
This systematic review identified 12 studies addressing the impact of HDT with ASCT in RMS. No prospective randomised trials were identified, and studies largely comprise retrospective data from American and European sarcoma registries.
High-dose chemotherapy as part of first-line treatment
Seven first-line treatment studies, which included two prospective non-randomised studies, provided survival results including EFS (n = 1) and both EFS and OS (n = 6) (7-13)(Table 5). The outcomes of two prospective non randomised cooperative studies in Europe, MMT4-89 and MMT4-91, of paediatric patients with metastatic stage IV RMS were analysed twice, in 1999 (9) and 2004 (8) respectively. Both studies found that HDT, given as consolidation after complete remission, did not significantly improve OS or EFS. In 1999, Carli et al. reported a 3-year OS of 29.7% for HDT (n = 52) versus 19.2% for conventional chemotherapy (n = 44, P = 0.3) and 3-year EFS of 40% for HDT versus 27.7% for conventional chemotherapy (P = 0.2) in 96 patients with primary stage IV RMS (9). The 2004 study (8) yielded similar results; documenting a 5-year OS of 36% (95% CI 23-49%) for HDT (n = 94) versus 27% (95% CI 14-41%) for conventional chemotherapy (n = 79) and a 5-year EFS of 29% (95% CI 16-41%) for HDT versus 23% (95% CI 11-36%) for conventional chemotherapy in 174 enrolled patients. Kim et al. retrospectively reviewed outcomes of 37 high risk RMS paediatric and adolescent patients (age 6 month to 15 years), with stage III or IV disease, of which 13 underwent HDT with ifosfamide/ carboplatin/ etoposide and ASCT. They found an improvement in 5-year EFS of 41.3% (SD +/-17.8%) in the 13 patients who underwent HDT versus 16.7% (SD +/-7.6%) in 24 patients who underwent conventional chemotherapy as part of first line treatment (p= 0.023) (10). The remaining RMS studies contribute with a lower level of evidence: three studies are non-controlled, and two of them include patients in the first-line and relapse setting (7, 11, 12) and one additional study has a very small sample size of only 17 patients (13).
Four heterogenous studies that grouped RMS and RMS-like tumours provided survival results in first-line treatment (Table 6). Hosoi et al. retrospectively reviewed 331 patients that were classified as per the Intergroup RMS Study V (IRS-V) risk group classification. They found a significant 5-year overall survival benefit for HDT in patients in the primary high-risk group, defined as having primary metastatic disease at diagnosis or undifferentiated sarcoma (58.2% versus 18.4%; HR 0.38, 95% CI 0.17-0.88, in 42 patients of which 22 received HDT) but not in intermediate-risk subgroup B tumours (5-year OS of 61.6% versus 54.5%; HR 0.82, 95% CI 0.38-1.77, in 88 patients of which 41 received HDT (14). In this study, the majority of patients (301 of 331) were determined to have a histological diagnosis of RMS. Further histopathological subtyping identified 67 and 117 patients with alveolar and embryonal pathology respectively. No significant difference in OS rates was seen in patients with embryonal and alveolar histological subtypes but notably, the FOX01 fusion status was known in only 10% of cases. In a prospective, non-randomised study of 96 children with primary metastatic soft tissue sarcoma (predominantly confirmed RMS), the efficacy of HDT was compared with oral maintenance chemotherapy (CWS-96 trial) after a standardised regimen. Forty-five patients received HDT in a non-randomised fashion, initiated at the discretion of the responsible physician. Klingebiel et al. found a decrease in OS with HDT compared to an oral maintenance regimen (OS 0.27 versus 0.52, p = 0.03) (15). The study included 45, 29, 14 and 8 patients with ARM, ERMS, ‘RMS-like’ and ‘non-RMS-like’ patients respectively. For the oral maintenance regimen, patients were treated with two additional courses of carboplatin, epirubicin, vincristine, ifosfamide, dactinomycin, etoposide (CEVAIE) before receiving alternating 10-day courses of trofosfamide and idarubicine (TI) and trofosfamide and etoposide (TE) for 24 weeks. The remaining two studies had no comparison group (16, 17).
Univariate and multivariate analysis in first line studies
Seven RMS and RMS-like tumour first-line studies reported significant findings following univariate and multivariate analysis. Several variables were found to be associated with improved outcomes following HDT with ASCT. Kim et al. found that 5-year EFS was higher in patients with RMS who achieved complete response or very good partial response at the time of ASCT (50.0% ± 20.4% vs. 37.5% ± 28.6% for other patients) (10). The treatment effect was observed to be greatest in the very high-risk group. Similarly, Matsubara et al. found a 5-year OS rate of 70% for 14 RMS patients who received HDT and ASCT in complete response versus 0% for 8 patients in partial response or with progressive disease (11). In parallel, Kingebiel et al. found that oral maintenance therapy was superior to HDT in the settings of tumour size > 5 cm, T2 tumours (extension and/or fixative to surrounding tissue) and when regional lymph nodes, bone and bone marrow were not involved (15).
High-dose chemotherapy for relapse/refractory disease
Only three studies included patients with relapsed/refractory disease. These were all retrospective case series of small number of patients (n=4, 22 and 62 respectively) and also included patient receiving HDT as part of first-line treatment (6, 11, 12) (Table 5). It is therefore not possible to draw any conclusion from these studies.
High-dose chemotherapy toxicities, treatment related mortality and secondary malignancies
Eleven studies provided information on treatment toxicity; however, toxicities were generally not reported comprehensively and only two provided a comparison of toxicities in each treatment group (10, 15).
Severe haematological toxicities were reported with HDT (8, 10, 11). Carli et al. (2004) cited myelosuppression as the most frequent adverse effect of HDT with 83%, 60%, and 45% of patients developing grade 3 or 4 neutropenia, thrombocytopenia, and anaemia, respectively. Kim et al. and Matsubara et al. described that all patients experienced severe myelosuppression (defined by Kim et al. as grade 3 or 4 haematological complication) with Matsubara et al. describing median durations of neutropenia <0.5x109/L and thrombocytopenia <50x109/L of 13 (9–20) and 29 (13–71) days, respectively.
In the two studies where a comparison of toxicities in each treatment group was provided, Kim et al. stated that haematologic complications were seen in both conventional chemotherapy or HDT/ASCT without statistical differences (10). Klingebiel et al. stated ‘the toxicity of either applied regimen was low’ though multiple grade 3 and 4 toxicities with HDT were recorded in supplementary material (15).
Treatment related deaths were recorded in 10 of the 11 studies that commented on treatment related toxicity. Treatment related mortality was 0 to 4% (Table 5&6) (6-12, 15-17). The largest study reported 6 toxic deaths amongst 174 patients, including 4 from sepsis and 2 from anthracycline-related cardiotoxicity, with no details given on their treatment group (8). Carli et al. (1999) reported 1 death in both the HDT and conventional chemotherapy groups. Kim et al. reported no death in the HDT group and 1 death in the conventional chemotherapy group. Klingebiel et al. reported 1 death in the HDT arm and no death in the conventional chemotherapy group (9, 10, 15).
Only two studies considered secondary malignancies. Yamada et al. reported two patients who developed secondary malignancies following HDT, and Matsubara et al. observed no secondary malignancy over a median follow-up time of 99 months (11, 17).
Discussion
This systematic review identified twelve studies addressing the impact of HDT with ASCT in RMS. Studies include only RMS patients with high risk and or metastatic primary disease, and minimal evidence was available for HDT in relapsed and refractory disease. There were no randomised prospective studies and available studies are largely based on retrospective data from American and European sarcoma registries. Most studies reported OS. Toxicities of HDT were not reported comprehensively.
HDT does not appear to confer a clear survival benefit in RMS. Two large prospective non-randomised cooperative studies from Europe suggested no improvement in overall or event-free survival following HDT with ASCT in patients with primary metastatic disease (8, 9). Two studies, by Hosoi et al. and Kim et al., report improved overall survival outcomes in the high-risk patients however these were retrospective analyses of small size (22 and 13 high risk patients received HDT, in Hosoi and Kim studies, respectively) (10, 14). Due to the relatively small number of high-quality comparative studies focused on RMS, it is difficult to infer the utility of HDT in treating relapsed disease. Broadly, high-quality randomised trials are required to clarify the survival benefit of HDT with ASCT in metastatic and in relapsed/refractory RMS.
In conclusion, HDT with ASCT has no proven benefit in high risk and metastatic primary RMS, or relapsed/refractory RMS, with conflicting evidence in the former and an absence of evidence in the latter. Prospective randomised clinical trials are required to clarify the survival benefit (or lack thereof) of HDT in RMS. As such, HDT is not recommended in patients with RMS unless enrolled in clinical trials.
Evidence Summary |
Level |
References |
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High-dose chemotherapy with autologous stem cell transplant has no proven survival benefit in primary localised, metastatic or relapsed rhabdomyosarcoma. |
III, IV |
(6, 8-15) |
Evidence-based recommendation |
Grade |
|
|
Patients with rhabdomyosarcoma should not undergo high dose chemotherapy outside of a clinical trial setting. |
C |
|
Practice point |
||
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Prospective high-quality trials are required to clarify the role of high dose chemotherapy in rhabdomyosarcoma. |
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* National Health and Medical Research Council. NHMRC levels of evidence and grades for recommendations for developers of guidelines. Canberra: NHMRC; 2009.