Recurrent Childhood Rhabdomyosarcoma

Current Clinical Trials

Although patients with recurrent or progressive rhabdomyosarcoma sometimes achieve complete remission with secondary therapy, the long-term prognosis is usually poor.[1,2] The prognosis is most favorable (50% to 70% 5-year survival rates) for children who initially present with Stage 1 or Group I disease and embryonal histology and who have small tumors, and for those who have a local or regional nodal recurrence.[1-3] The small number of children with botryoid histology who relapse have a similarly favorable prognosis.[1] Most other children who relapse have an extremely poor prognosis.[1] A retrospective review of rhabdomyosarcoma patients from German soft tissue sarcoma trials identified time to recurrence as an important independent prognostic factor. Shorter time to recurrence was associated with higher risk of mortality from recurrent rhabdomyosarcoma.[4][Level of evidence: 3iiB] European investigators performed a retrospective review of patients with rhabdomyosarcoma enrolled on cooperative group trials who experienced recurrence. They identified metastatic (as opposed to local) recurrence, prior radiation therapy, initial tumor size (>5 cm), and time to relapse (<18 months) as unfavorable prognostic features for survival after recurrence.[5]

The selection of further treatment depends on many factors, including the site(s) of recurrence, previous treatment, and individual patient considerations. Treatment for local or regional recurrence may include wide local excision or aggressive surgical removal of tumor, particularly in the absence of widespread bony metastases.[6,7] Some survivors have also been reported after surgical removal of only one or a few metastases in the lung.[6] Radiation therapy should be considered for patients who have not already received radiation therapy in the area of recurrence, or rarely for those who have received radiation therapy but for whom surgical excision is not possible. Previously unused, active, single agents or combinations of drugs may also enhance the likelihood of disease control.

The following standard chemotherapy regimens have been used to treat recurrent rhabdomyosarcoma:

• Carboplatin/etoposide.[8]

• Ifosfamide, carboplatin, and etoposide.[9,10]

• Cyclophosphamide/topotecan.[11]

• Irinotecan with or without vincristine.[12-15] A Children's Oncology Group (COG) prospective, randomized, up-front window trial, COG-ARST0121, showed no difference between vincristine plus irinotecan (20 mg/m²/d) daily × 5 days for 4 weeks per 6-week treatment cycle (Regimen 1A) and irinotecan (50 mg/m²/d) daily × 5 days for 2 weeks per 6-week treatment cycle (Regimen 1B) in poor-risk patients with relapsed or progressive rhabdomyosarcoma. At 1 year after initiation of treatment for recurrence, the failure-free survival (FFS) rate was 37% and the overall survival rate (OS) was 55% for Regimen 1A; the FFS rate was 38% and OS rate was 60% for Regimen 1B. The Soft Tissue Sarcoma Committee of the COG recommended the more convenient Regimen 1B for further investigation.[16][Level of evidence: 1iiA]

• Single-agent vinorelbine. In one phase II trial, four of eleven patients with recurrent rhabdomyosarcoma responded to single-agent vinorelbine.[17] In another trial, 6 of 12 young patients (aged 9–29 years) had a partial response.[18]

• Vinorelbine and cyclophosphamide. In a pilot study, three patients (N = 9) with rhabdomyosarcoma had an objective response.[19]

• Gemcitabine and docetaxel. In a single institution trial, two patients (N = 5) with recurrent rhabdomyosarcoma achieved an objective response.[20]

• Rapamycin.[21]

• Topotecan, vincristine, and doxorubicin.[22][Level of evidence: 3iiiDiv]

Treatment options under clinical evaluation for recurrent rhabdomyosarcoma:

• COG-ARST0921 (Vinorelbine Ditartrate and Cyclophosphamide in Combination With Bevacizumab or Temsirolimus in Treating Patients With Recurrent or Refractory Rhabdomyosarcoma): A randomized phase II trial for patients experiencing their first relapse or progression of rhabdomyosarcoma. The goals of this study are to determine the feasibility of administering bevacizumab or temsirolimus with a chemotherapy regimen of intravenous vinorelbine and cyclophosphamide and to compare the event-free survival of patients treated with vinorelbine/cyclophosphamide plus temsirolimus and those treated with vinorelbine/cyclophosphamide plus bevacizumab.

• COG-ADVL1121 (Sorafenib Tosylate in Treating Younger Patients With Relapsed or Refractory Rhabdomyosarcoma, Wilms Tumor, Liver Cancer, or Thyroid Cancer): A phase II study of sorafenib, a Raf kinase and receptor tyrosine kinase inhibitor, for children and young adults with relapsed/refractory rhabdomyosarcoma, Wilms tumor, hepatocellular carcinoma, and papillary thyroid carcinoma. The goal of this study is to determine the objective response rate of sorafenib in children with refractory or relapsed rhabdomyosarcoma. Patients must be aged 2 to 30 years.

• Intensive chemotherapy followed by autologous bone marrow transplantation. Very intensive chemotherapy followed by autologous bone marrow reinfusion is also under investigation for patients with recurrent rhabdomyosarcoma. However, a review of the published data did not determine a significant benefit for patients who underwent this salvage treatment approach.[23-25]

• New agents under clinical evaluation in phase I and phase II trials should be considered for relapsed patients.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with recurrent childhood rhabdomyosarcoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

1. Pappo AS, Anderson JR, Crist WM, et al.: Survival after relapse in children and adolescents with rhabdomyosarcoma: A report from the Intergroup Rhabdomyosarcoma Study Group. J Clin Oncol 17 (11): 3487-93, 1999.  [PUBMED Abstract]
   
   
2. Mazzoleni S, Bisogno G, Garaventa A, et al.: Outcomes and prognostic factors after recurrence in children and adolescents with nonmetastatic rhabdomyosarcoma. Cancer 104 (1): 183-90, 2005.  [PUBMED Abstract]
   
   
3. Dantonello TM, Int-Veen C, Winkler P, et al.: Initial patient characteristics can predict pattern and risk of relapse in localized rhabdomyosarcoma. J Clin Oncol 26 (3): 406-13, 2008.  [PUBMED Abstract]
   
   
4. Mattke AC, Bailey EJ, Schuck A, et al.: Does the time-point of relapse influence outcome in pediatric rhabdomyosarcomas? Pediatr Blood Cancer 52 (7): 772-6, 2009.  [PUBMED Abstract]
   
   
5. Chisholm JC, Marandet J, Rey A, et al.: Prognostic factors after relapse in nonmetastatic rhabdomyosarcoma: a nomogram to better define patients who can be salvaged with further therapy. J Clin Oncol 29 (10): 1319-25, 2011.  [PUBMED Abstract]
   
   
6. Hayes-Jordan A, Doherty DK, West SD, et al.: Outcome after surgical resection of recurrent rhabdomyosarcoma. J Pediatr Surg 41 (4): 633-8; discussion 633-8, 2006.  [PUBMED Abstract]
   
   
7. De Corti F, Bisogno G, Dall'Igna P, et al.: Does surgery have a role in the treatment of local relapses of non-metastatic rhabdomyosarcoma? Pediatr Blood Cancer 57 (7): 1261-5, 2011.  [PUBMED Abstract]
   
   
8. Klingebiel T, Pertl U, Hess CF, et al.: Treatment of children with relapsed soft tissue sarcoma: report of the German CESS/CWS REZ 91 trial. Med Pediatr Oncol 30 (5): 269-75, 1998.  [PUBMED Abstract]
   
   
9. Kung FH, Desai SJ, Dickerman JD, et al.: Ifosfamide/carboplatin/etoposide (ICE) for recurrent malignant solid tumors of childhood: a Pediatric Oncology Group Phase I/II study. J Pediatr Hematol Oncol 17 (3): 265-9, 1995.  [PUBMED Abstract]
   
   
10. Van Winkle P, Angiolillo A, Krailo M, et al.: Ifosfamide, carboplatin, and etoposide (ICE) reinduction chemotherapy in a large cohort of children and adolescents with recurrent/refractory sarcoma: the Children's Cancer Group (CCG) experience. Pediatr Blood Cancer 44 (4): 338-47, 2005.  [PUBMED Abstract]
    
    
11. Saylors RL 3rd, Stine KC, Sullivan J, et al.: Cyclophosphamide plus topotecan in children with recurrent or refractory solid tumors: a Pediatric Oncology Group phase II study. J Clin Oncol 19 (15): 3463-9, 2001.  [PUBMED Abstract]
    
    
12. Cosetti M, Wexler LH, Calleja E, et al.: Irinotecan for pediatric solid tumors: the Memorial Sloan-Kettering experience. J Pediatr Hematol Oncol 24 (2): 101-5, 2002.  [PUBMED Abstract]
    
    
13. Pappo AS, Lyden E, Breitfeld P, et al.: Two consecutive phase II window trials of irinotecan alone or in combination with vincristine for the treatment of metastatic rhabdomyosarcoma: the Children's Oncology Group. J Clin Oncol 25 (4): 362-9, 2007.  [PUBMED Abstract]
    
    
14. Vassal G, Couanet D, Stockdale E, et al.: Phase II trial of irinotecan in children with relapsed or refractory rhabdomyosarcoma: a joint study of the French Society of Pediatric Oncology and the United Kingdom Children's Cancer Study Group. J Clin Oncol 25 (4): 356-61, 2007.  [PUBMED Abstract]
    
    
15. Furman WL, Stewart CF, Poquette CA, et al.: Direct translation of a protracted irinotecan schedule from a xenograft model to a phase I trial in children. J Clin Oncol 17 (6): 1815-24, 1999.  [PUBMED Abstract]
    
    
16. Mascarenhas L, Lyden ER, Breitfeld PP, et al.: Randomized phase II window trial of two schedules of irinotecan with vincristine in patients with first relapse or progression of rhabdomyosarcoma: a report from the Children's Oncology Group. J Clin Oncol 28 (30): 4658-63, 2010.  [PUBMED Abstract]
    
    
17. Kuttesch JF Jr, Krailo MD, Madden T, et al.: Phase II evaluation of intravenous vinorelbine (Navelbine) in recurrent or refractory pediatric malignancies: a Children's Oncology Group study. Pediatr Blood Cancer 53 (4): 590-3, 2009.  [PUBMED Abstract]
    
    
18. Casanova M, Ferrari A, Spreafico F, et al.: Vinorelbine in previously treated advanced childhood sarcomas: evidence of activity in rhabdomyosarcoma. Cancer 94 (12): 3263-8, 2002.  [PUBMED Abstract]
    
    
19. Casanova M, Ferrari A, Bisogno G, et al.: Vinorelbine and low-dose cyclophosphamide in the treatment of pediatric sarcomas: pilot study for the upcoming European Rhabdomyosarcoma Protocol. Cancer 101 (7): 1664-71, 2004.  [PUBMED Abstract]
    
    
20. Rapkin L, Qayed M, Brill P, et al.: Gemcitabine and docetaxel (GEMDOX) for the treatment of relapsed and refractory pediatric sarcomas. Pediatr Blood Cancer 59 (5): 854-8, 2012.  [PUBMED Abstract]
    
    
21. Houghton PJ, Morton CL, Kolb EA, et al.: Initial testing (stage 1) of the mTOR inhibitor rapamycin by the pediatric preclinical testing program. Pediatr Blood Cancer 50 (4): 799-805, 2008.  [PUBMED Abstract]
    
    
22. Meazza C, Casanova M, Zaffignani E, et al.: Efficacy of topotecan plus vincristine and doxorubicin in children with recurrent/refractory rhabdomyosarcoma. Med Oncol 26 (1): 67-72, 2009.  [PUBMED Abstract]
    
    
23. Weigel BJ, Breitfeld PP, Hawkins D, et al.: Role of high-dose chemotherapy with hematopoietic stem cell rescue in the treatment of metastatic or recurrent rhabdomyosarcoma. J Pediatr Hematol Oncol 23 (5): 272-6, 2001 Jun-Jul.  [PUBMED Abstract]
    
    
24. Admiraal R, van der Paardt M, Kobes J, et al.: High-dose chemotherapy for children and young adults with stage IV rhabdomyosarcoma. Cochrane Database Syst Rev (12): CD006669, 2010.  [PUBMED Abstract]
    
    
25. Peinemann F, Kröger N, Bartel C, et al.: High-dose chemotherapy followed by autologous stem cell transplantation for metastatic rhabdomyosarcoma--a systematic review. PLoS One 6 (2): e17127, 2011.  [PUBMED Abstract]