Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma

doi:10.1016/j.ejca.2009.08.019

European Journal of Cancer

Volume 45, Issue 17, November 2009, Pages 3035-3041

https://doi.org/10.1016/j.ejca.2009.08.019 Get rights and content

Abstract

Aim

The RMS4.99 study was designed to explore the role of multiple sequential high-dose chemotherapy cycles administered early in the treatment of children with metastatic rhabdomyosarcoma.

Patients and methods

Seventy patients were enrolled and received three cycles of initial standard chemotherapy, followed by a course of cyclophosphamide and etoposide to obtain peripheral blood stem cells (PBSC), then three consecutive high-dose combinations followed by PBSC rescue. This was followed by surgery and/or radiotherapy, after which a final maintenance treatment with six courses of vincristine, actinomycin D and cyclophosphamide was administered.

Results

Sixty-two patients underwent the high-dose chemotherapy phase. The 3-year overall survival (OS) and progression free survival (PFS) rates for the 70 patients were 42.3% (95% confidence interval [CI] 39.5–53.6) and 35.3% (95% CI, 24.3–46.5), respectively. By multivariate analysis survival correlated strongly with age > 10 years. In a subset of patients with only one or no unfavourable prognostic factors (age > 10 years, unfavourable site of primary tumour, bone or bone marrow involvement and number of metastatic sites >2) the PFS was significantly higher, i.e. 60.5% at 3 years.

Conclusion

Our study confirms that patients with favourable prognostic characteristics have a better survival. The use of sequential cycles of high-dose chemotherapy did not appear of benefit for patients with metastatic rhabdomyosarcoma.

Introduction

The prognosis for children with cancer has improved dramatically in the last 30 years, but there are still certain types of patients for whom little or no progress has been made. Children with metastatic rhabdomyosarcoma (RMS) are among them, with 3-year event-free survival rates ranging from 20 to 30%.1, 2, 3 These figures have not changed over time, despite the use of new drugs and the intensification of treatment. There is consequently an evident need for novel strategies.

In an attempt to overcome drug resistance, high-dose chemotherapy with stem cell rescue has been tested in patients with malignancies that carry a poor prognosis. A benefit has emerged in children with metastatic neuroblastoma,⁴ while it remains uncertain for other solid tumours.

In RMS, megatherapy has been used as a consolidation treatment in children achieving complete tumour remission after intensive chemotherapy, but unfortunately no significant improvement in survival has been obtained.5, 6

In 1999, the Soft Tissue Sarcoma Committee (STSC), affiliated to the Associazione Italiana di Ematologia e Oncologia Pediatrica (AIEOP), started its RMS4.99 study, based on the hypothesis that administering high-dose chemotherapy earlier than in previous experiences might help to prevent the occurrence of drug resistance and improve survival.

Section snippets

Patients and methods

As of September 2006, 70 eligible patients with metastatic RMS, ranging in age from 0.9 months to 20.9 years (median 9.4 years), had been enrolled on the RMS4.99 protocol. Histology was reviewed centrally by the STSC pathology panel. The extent of the primary tumour was assessed according to the TNM pretreatment staging system, where T1 refers to tumours confined to the organ or tissue of origin, while T2 lesions invade contiguous structures; T1 and T2 tumours are further classified as A or B

Results

The clinical characteristics of the study population are given in Table 1. As expected, alveolar RMS was more common, most tumours being large (85% > 5 cm) and invasive (69% T2). The primary tumour was most often located in the extremities (26%), and abdomen/pelvis (22%), both generally considered unfavourable sites.

The distribution of metastases was as usual, the lung (45% of patients), bone (38%) and bone marrow (31%) being the most frequently involved organs, and were the only metastatic

Discussion

The prognosis for patients with metastatic RMS has improved very little over the years, despite investigators’ attempts to use different therapeutic approaches. Strategies to improve the outcome for these patients have included adding active agents, such as anthracyclines, platinum derivatives and etoposide,7, 10 to standard chemotherapy, but to no apparent benefit.

The search for new drugs or more effective multidrug combinations has been conducted systematically by the Intergroup

Conflict of interest statement

None declared.

Acknowledgements

The authors thank Angela Scagnellato for her continuous support in data processing and Gloria Tridello for the statistical analysis.This research was supported by a grant from the Fondazione Città della Speranza.

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Patients with high-risk or metastatic Ewing sarcoma (ES) and rhabdomyosarcoma (RMS) have a guarded prognosis. High-dose chemotherapy (HDT) with autologous stem cell transplant (ASCT) has been evaluated as a treatment option to improve outcomes. However, survival benefits remain unclear, and treatment is associated with severe toxicities.
A systematic review was conducted, using the population, intervention, comparison outcome (PICO) model, to evaluate whether utilization of HDT/ASCT impacts the outcome of patients with ES and RMS compared to standard chemotherapy alone, as part of first line treatment or in the relapse setting. Medline, Embase and Cochrane Central were queried for publications from 1990 to October 2022 that evaluated event-free survival (EFS), overall survival (OS), and toxicities. Each study was screened by two independent reviewers for suitability. A qualitative synthesis of the results was performed.
Of 1,172 unique studies screened, 41 studies were eligible for inclusion with 29 studies considering ES, 10 studies considering RMS and 2 studies considering both. In ES patients with high-risk localised disease who received HDT/ASCT after VIDE chemotherapy, consolidation with melphalan-based HDT/ASCT as first line therapy conveyed an EFS and OS benefit over standard chemotherapy consolidation. Efficacy of HDT/ASCT using a VDC/IE backbone, which is now standard care, has not been established. Survival benefits are not confirmed for ES patients with metastatic disease at initial diagnosis. For relapsed/refractory ES, four retrospective studies report improvement in outcomes with HDT/ASCT with the greatest evidence in patients who demonstrate a treatment response before HDT, and in patients under the age of 14. In RMS, there is no proven survival benefit of HDT/ASCT in primary localised, metastatic or relapsed disease.
Prospective randomised trials are required to determine the utility of HDT/ASCT in ES and RMS. Selected patients with relapsed ES could be considered for HDT/ASCT.
Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma
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Pediatric patients with relapsed or refractory rhabdomyosarcoma (RMS) have dismal cure rates, and effective therapy is urgently needed. The oncogenic receptor tyrosine kinase fibroblast growth factor receptor 4 (FGFR4) is highly expressed in RMS and lowly expressed in healthy tissues. Here, we describe a second-generation FGFR4-targeting chimeric antigen receptor (CAR), based on an anti-human FGFR4-specific murine monoclonal antibody 3A11, as an adoptive T cell treatment for RMS. The 3A11 CAR T cells induced robust cytokine production and cytotoxicity against RMS cell lines in vitro. In contrast, a panel of healthy human primary cells failed to activate 3A11 CAR T cells, confirming the selectivity of 3A11 CAR T cells against tumors with high FGFR4 expression. Finally, we demonstrate that 3A11 CAR T cells are persistent in vivo and can effectively eliminate RMS tumors in two metastatic and two orthotopic models. Therefore, our study credentials CAR T cell therapy targeting FGFR4 to treat patients with RMS.
Deep learning enabled prediction of 5-year survival in pediatric genitourinary rhabdomyosarcoma
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Indeed, patients with low-risk disease have attained 3-year survival rates of greater than 95% with modern treatment paradigms [3]. However, for patients with metastatic and/or relapsed disease, survival rates remain poor, with a 3-year overall survival ranging from 34% to 42% [4,5]. GU-RMS patients proceed along a risk-stratified treatment regimen, with patients classified as low-risk, intermediate-risk, or high-risk based on site of disease, histology, and TNM staging.
Genitourinary rhabdomyosarcoma (GU-RMS) is a rare, pediatric malignancy originating from embryonic mesenchyme. Current approaches to prognostication rely upon conventional statistical methods such as Cox proportional hazards (CPH) models and have suboptimal predictive ability. Given the success of deep learning approaches in other specialties, we sought to develop and compare deep learning models with CPH models for the prediction of 5-year survival in pediatric GU-RMS patients.
Patients less than 20 years of age with GU-RMS were identified within the Surveillance, Epidemiology, and End Results (SEER) database (1998–2011). Deep neural networks (DNN) were trained and tested on an 80/20 split of the dataset in a 5-fold cross-validated fashion. Multivariable CPH models were developed in parallel. The primary outcomes were 5-year overall survival (OS) and disease-specific survival (DSS). Variables used for prediction were age, sex, race, primary site, histology, degree of tumor extension, tumor size, receipt of surgery, and receipt of radiation. Receiver operating characteristic curve analysis was conducted, and DNN models were tested for calibration.
277 patients were included. The area under the curve (AUC) for the DNN models was 0.93 for OS and 0.91 for DSS. AUC for the CPH models was 0.82 for OS and 0.84 for DSS. The DNN models were well-calibrated: OS model (slope = 1.02, intercept = −0.06) and DSS model (slope = 0.79, intercept = 0.21).
A deep learning-based model demonstrated excellent performance, superior to that of CPH models, in the prediction of pediatric GU-RMS survival. Deep learning approaches may enable improved prognostication for patients with rare cancers.
Fifty years of rhabdomyosarcoma studies on both sides of the pond and lessons learned
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Multiple cycles of HD-CT were sequentially administered early in the treatment (after the initial 3 courses). Unfortunately the 3-year PFS was 35%, not much better than previous [49]. In the SIOP MMT 98 study, standard CEVAIE was followed by multiple cycles of sequential high-dose monotherapy with cyclophosphamide, etoposide and carboplatin in patients aged >10 years or bone/bone marrow involvement.
We review and summarize the highlights of almost five decades of cooperative group trials in rhabdomyosarcoma on both sides of the Atlantic, concentrating on chemotherapy regimens, what has been learned, and where remaining challenges are. The most important achievements have been to decrease or omit the dose of alkylator therapy for many patients, to clarify after much controversy that doxorubicin does not improve the outcome of patients even in the highest risk groups, and to show that high dose chemotherapy and stem cell rescue do not improve the outcome of the highest risk patients. In North America, vincristine/actinomycin/cyclophosphamide (VAC) remains an important part of therapy, whereas in Europe the alkylating agent of choice is ifosfamide. The highest risk patients, namely those with the poorest prognostic score, have had no improvement in outcome since the first cooperative group trial in 1972 and remain the greatest challenge. Philosophical differences between European and North American strategies still revolve somewhat around the total burden of therapy received, that is should certain groups of patients be spared aggressive local control in order to reduce late effects, recognizing that it is not possible to identify priori the children that can be cured with this approach exposing the whole population to a higher risk of relapse. Collaboration and joining resources may help answer some difficult questions.
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The role of high-dose chemotherapy followed by stem cell rescue (HDSCT) remains undefined in the treatment of metastatic RMS. Several European studies have not supported the use of HDSCT for high-risk patients [58–60]. Interestingly, the German HD CWS-96 trial demonstrated that patients with metastatic RMS, who received oral maintenance chemotherapy with trofosfamide plus etoposide alternating with trofosfamide plus idarubicin, had an improved survival rate at a median follow-up of 57.4 months compared with patients who received HDSCT (57.8% vs. 24%) [59].
Rhabdomyosarcoma (RMS) represents the most common soft tissue sarcoma in infants and children and the third most common pediatric solid tumor, accounting for 5% to 15% of all childhood solid tumors. Of these, 15% to 20% arise from the genitourinary tract, with the most common sites originating from the prostate, bladder, and paratesticular regions, followed by the vagina and uterus. Although upfront radical surgery was used at the initiation of Intergroup RMS Study-I (1972–1978), the treatment paradigm has shifted to include initial biopsy with the goal of organ preservation, systemic chemotherapy for all patients, and local control involving surgical resection with or without radiation therapy for most patients. Collaborative group clinical trials have led to dramatic improvement in survival rates from 1960 to 1996 among patients with low- or intermediate-risk disease; however, outcomes appear to have plateaued in more recent years, and the prognosis for patients with metastatic or relapsed/refractory disease remains poor.
Current management goals include minimizing toxicity while maintaining the excellent outcomes in low-risk disease, as well as improving outcomes in patients with intermediate- and high-risk disease. Advances in genetic analysis have allowed further refinement in risk stratification of patients. Perhaps the most significant recent development in RMS research was the discovery of an association of alveolar RMS (ARMS) with translocations t(2;13) and t(1;13). Translocation fusion-positive tumors comprise 80% of ARMS and are more aggressive. Fusion-negative ARMS may have a clinical course similar to embryonal RMS. Future Children׳s Oncology Group sarcoma studies will likely incorporate fusion status into risk stratification and treatment allocation.
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Osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma are the most common malignant musculoskeletal tumors in children and adolescents. Today, most patients can be cured. Numerous factors have contributed to improved outcome for these patients over the past several decades. These include multidisciplinary care involving oncologists, radiation oncologists, surgeons, pathologists, and radiologists and enrollment of patients in clinical trials. Better understanding of molecular mechanisms of disease have resulted in studies using molecular targets in addition to standard chemotherapeutic agents, which hopefully will lead to better outcomes in the future. Moreover, new orthopedic techniques and devices as well as new technologies in radiation oncology hold promise for better local control of primary tumors and the potential for fewer late adverse effects. Despite this progress, patients must undergo lifelong follow-up for possible late effects of intense chemotherapy and radiation therapy. We review the diagnosis, prognosis, staging, multidisciplinary therapy, new directions in therapy, and long-term complications of treatment for these tumors. For this review, we searched MEDLINE using the terms rhabdomyosarcoma, osteosarcoma, Ewing sarcoma, biology, and humans and limited the search to articles from 2000 to September 2011. Additional references found in these articles were utilized as appropriate, as well as references from the background information in current therapeutic studies of the Children's Oncology Group. The same database and time frame were searched for articles written by leading authorities in the field.

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European Journal of Cancer

Abstract

Aim

Patients and methods

Results

Conclusion

Introduction

Section snippets

Patients and methods

Results

Discussion

Conflict of interest statement

Acknowledgements

References (21)

European Intergroup Studies (MMT4–89 and MMT4–91) on childhood metastatic rhabdomyosarcoma: final results and analysis of prognostic factors

J Clin Oncol

Prognostic factors and clinical outcomes in children and adolescents with metastatic rhabdomyosarcoma - a report from the Intergroup Rhabdomyosarcoma Study IV

J Clin Oncol

Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma

J Pediatr Hematol Oncol

High-dose melphalan with autologous stem-cell rescue in metastatic rhabdomyosarcoma

J Clin Oncol

Metastatic rhabdomyosarcoma and histologically similar tumors in childhood: a retrospective European multicentre analysis

Med Pediatr Oncol

Response of previously untreated metastatic rhabdomyosarcoma to combination chemotherapy with carboplatin, epirubicin and vincristine

Eur J Cancer

The IVADo regimen - a pilot study with ifosfamide, vincristine, actinomycin D, and doxorubicin in children with metastatic soft tissue sarcoma: a pilot study on behalf of the European pediatric Soft tissue sarcoma Study Group

Cancer

Prognostic factors in metastatic rhabdomyosarcomas: results of a pooled analysis from United States and European cooperative groups

J Clin Oncol

The Third Intergroup Rhabdomyosarcoma Study

J Clin Oncol

Cited by (32)

High-dose chemotherapy for Ewing sarcoma and Rhabdomyosarcoma: A systematic review by the Australia and New Zealand sarcoma association clinical practice guidelines working party

Preclinical development of a chimeric antigen receptor T cell therapy targeting FGFR4 in rhabdomyosarcoma

Deep learning enabled prediction of 5-year survival in pediatric genitourinary rhabdomyosarcoma

Fifty years of rhabdomyosarcoma studies on both sides of the pond and lessons learned

Future directions in risk stratification and therapy for advanced pediatric genitourinary rhabdomyosarcoma

Common musculoskeletal tumors of childhood and adolescence