Malignant Rhabdoid Tumor Treatment & Management

Updated: Sep 27, 2021
  • Author: James I Geller, MD, FAAP; Chief Editor: Max J Coppes, MD, PhD, MBA  more...
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Medical Care

After the primary tumor is surgically removed, chemotherapy and radiotherapy are indicated as adjuvant treatment for malignant rhabdoid tumor (MRT). Chemotherapy for MRT was historically based on therapy for a Wilms tumor, which included vincristine, actinomycin, and doxorubicin with or without cyclophosphamide. With these agents, the estimated survival rate for patients with MRT was only 23%.

To try to improve these results, investigators in NWTS-5 used a regimen consisting of carboplatin-etoposide alternating with cyclophosphamide. However, this strategy, did not improve outcomes. Subsequent case reports documented successful outcomes in patients with metastatic MRT treated with ifosfamide-carboplatin-etoposide (ICE) or ifosfamide-etoposide (IE) alternating with vincristine-doxorubicin-cyclophosphamide (VDC). On the basis of these reports, the most recent COG study AREN0321, regimen UH-1, used cyclophosphamide-carboplatin-etoposide (CCE) alternating with VDC. The 4-year event-free survival (EFS) and overall survival (OS) estimates for the entire cohort of patients were 23.1% and 33.33%, respectively, with a median time to progression of 2.7 months. [28] There was a trend toward improved outcomes for low stage patients (100% 4-year EFS for 2 patients with Stage 1 disease and 80% for 5 patients with Stage 2 disease), but continued dismal outcomes for those with higher stage disease.  

Insights into the treatment of MRT may be derived from the experience with atypical teratoid/rhabdoid tumors (AT/RT) of the CNS. Like its extra-CNS counterparts, AT/RT results in an unfavorable prognosis and is characterized by resistance to chemotherapy. Current treatment involves a multimodal approach with a combination of surgery, radiation therapy, and various chemotherapy regimens (systemic and intrathecal) that typically included cisplatin, etoposide, vincristine, ifosfamide, doxorubicin, actinomycin, cyclophosphamide, methotrexate, and intrathecal agents with or without autologous stem-cell rescue. These treatments have improved the survival rates of patients with AT/RT from historical controls.  

A review by Tekautz et al of children treated at St. Jude Children’s Research Hospital from 1984-2003 showed that AT/RT presenting in patients older than 3 demonstrated a 2-year event-free survival of 78% when treated with a combination of radiation and high-dose alkylating therapy. [31] Subsequently, the Dana Farber Consortium AT/RT study, which was a multisite study of multimodal therapy incorporating surgery, age- and stage-directed radiation, and a systemic and intrathecal conventional chemotherapeutic regimen based on a modified IRS-III regimen, demonstrated a 2-year progression-free survival of 53%. This later study included infants younger than 3 years of age. [32] Additionally, there are reports that describe the successful use of high-dose chemotherapy with stem cell rescue to treat non-CNS MRT. [33] Considering all data, the recently closed COG AT/RT protocol ACNS0333 used a regimen incorporating surgery, conventional chemotherapy, age- and stage-directed radiation, and three cycles of high-dose chemotherapy with stem cell rescue. This study showed an overall 2-year progression-free survival of 42% in the entire cohort and of 39% for those < 3 years of age. [34] In Europe, the registry study (Eu-Rhab) for all rhabdoid tumors (AT/RT, RTK, and MRT) recommends using combination therapy including surgery, radiotherapy, and chemotherapy with permissive use of high-dose chemotherapy with stem cell rescue. [35]

Furtwängler et al conducted a review of 3 prospective studies comparing the change of tumor volume as a result of treatment with either actinomycin D and vincristine combination therapy (AV) or doxorubicin-intensified actinomycin D and vincristine combination therapy (AVD) in all patients with MRT of the kidney who had been treated from 1991 to 2013 in Austria, Switzerland, and Germany. The investigators concluded that a significantly better treatment response is achieved with neoadjuvant AVD than with AV alone. [36]

Venkatramani et al discussed a potential role for higher dose alkylator therapy and/or high-dose chemotherapy with stem cell rescue for MRT patients, analogous to approaches for AT/RT, but no formal trial has demonstrated a therapeutic advantage in treatment of non-CNS MRT. [37] Based on the limited data available at this time, whether high-dose chemotherapy with stem cell rescue is of any added benefit for non-CNS MRT is unclear.

Similarly, anecdotal reports suggest a benefit from the use of radiotherapy as part of multimodal therapy for MRT. However, the lack of treatment uniformity among reported patients makes it difficult to determine if radiotherapy is effective for MRT outside the CNS. In NWTS 1-5, radiation therapy was given to the flank or abdomen at total doses of 1080-3500 cGy and to total doses of 1080-2100 cGy on AREN0321. However, the optimal dose remains to be determined. Nemes et al published an evaluation of 100 patients with extracranial MRT recruited within EU-RHAB from 2009-2018, which determined that administration of radiotherapy was statistically associated with favorable outcomes in univariate analysis (P = 0.0003), with a trend toward significance in multivariate analysis. [24] Radiation therapy is a cornerstone of treatment for CNS AT/RT, with use of radiation therapy being an independent predictor of overall survival (hazard ratio, 0.1; P = 0.02), with the benefit being more pronounced in patients < 3 years of age. [38]

In sum, while the prognosis for select patients, particularly those with localized MRT associated with an older age and lower stage disease, has improved, the overall outcomes of MRT remain poor despite maximized therapy intensity, leading to an emphasis on the integration of novel therapies that target the underlying biology as the next steps needed for advancements in cure for Stage 3 and 4 MRT patients.

Novel therapeutics

EZH2 is a histone methyltransferase that is upregulated in rhabdoid tumors. EZH2 can now be targeted with EZH2 inhibitors that have been shown to have anti-rhabdoid tumor effects both in vitro and in vivo. Tazemetostat (EPZ-6438), a selective, orally bioavailable, small molecule inhibitor of the EZH2 gene, has been shown to have pre-clinical and clinical activity in MRT. Knutson et al have shown that tazemetostat induces apoptosis and differentiation specifically in SMARCB1-depleted MRT cells and treatment of mice with the drug leads to dose-dependent regression of MRTs and prevention of regrowth after dosing cessation. [39] Additional pre-clinical investigations have demonstrated tazemetostat to have enhanced antitumor activity when administered in combination with chemotherapy regimens including vincristine, doxorubicin, and cyclophosphamide (Epizyme, Investigator Brochure, March 2016). In addition, the Pediatric Pre-clinical Testing Program (PPTP) published results showing significant antitumor activity of tazemetostat in MRT xenograft models (3/5 xenograft models), without demonstrable effect in the other histologies tested (0/22). [40] Clinical activity of tazemetostat has been shown in subjects with genetically defined SMARCB1 altered tumors, including those with epitheliod sarcoma and MRT of the ovary. The Phase 1 pediatric study EZH-102 evaluated the administration of tazemetostat to patients with relapsed/refractory MRT and other SMARCB1/SMARCB4 mutated tumors or synovial sarcoma. A recommended phase 2 dose was determined, and the study recently completed expansion phase enrollment; outcomes of this study have not yet been published, but results are forthcoming. This promising agent may be combined with a chemotherapy backbone for future clinical trials in MRT.

Cyclin dependent kinases (CDK) 4/6 activity is upregulated by the loss of SMARCB1 in MRTs. Ribociclib (LEE011) is an orally bioavailable, specific inhibitor of CDK4/6 that has been shown to have in vitro activity in MRT cell lines. A Phase 1 study of ribociclib in pediatric patients with neuroblastoma, MRT, or other cyclin D-CDK4/6-INK4-retinoblastoma pathway-altered tumors showed prolonged stable disease that supports further testing of ribociclib in combination with other agents. [41]

BRD9, which forms a subunit of the SWI/SNF complex, inhibition has been investigated by Krӓmer et al. [9] Two specific chemical probes (I-BRD9 and BI-9564) that selectively target BRD9 were evaluated in 5 MRT cell lines alone and in combination with cytotoxic drugs. Single compound treatment with I-BRD9 and BI-9864 resulted in decreased cell proliferation and apoptosis. Combined treatment of doxorubicin or carboplatin with I-BRD9 resulted in additive to synergistic inhibitor effects on cell proliferation. Therefore, BRD9 is an attractive target for novel therapeutic agents. [9]

CHK1 is a serine-threonine kinase that plays a central role in pausing cell cycle progression in response to DNA damage and/or replicative stress. Activation of CHK1 in response to single-stranded DNA breaks or stalled replication forks plays a central role in the G2-M and S-phase cell-cycle checkpoints. Prexasertib (LYS2606360) is a potent ATP-competitive CHK1 inhibitor that exhibits single agent cytotoxicity through replication catastrophe. [42] The PPTP tested prexasertib in mice bearing a MRT xenogradt and found it induced a maintained complete response for approximately 4 weeks after treatment was complete. In addition, the combination of prexasertib with irinotecan showed a significantly superior prolonged EFS in the MRT xenograt compared to irinotecan alone. [43] The COG Phase 1 clinical trial of prexasertib in pediatric patients with recurrent or refractory solid tumors has completed enrollment, and a recommended phase 2 dose was determined. [44] Further evaluation of prexasertib in combination with chemotherapy could be investigated. 

Utilization of immune checkpoint inhibitors is another promising area of research for MRT patients. In a study of 16 cases of relapsed MRT, 9 showed high tumor infiltrating lymphocytes with PD-1 staining ranging from 10-60%, correlating with PD-L1 staining. [45] It has also been noted that both human MRT and a mouse MRT model are highly infiltrated by immune cells of both lymphoid and myeloid lineages, with T-cell expressing PD-1 and tumor cells expressing PD-L1. In these models, blockade of the PD-1/PD-L1 pathway impaired tumor growth. [46] Therefore, immune checkpoint inhibitors could be investigated in MRT patients. 

MRT xenografts are being tested against new drugs through the PPTP, which will lead to continued development of novel therapeutic agents in the future.  



Surgical Care

Children with a renal tumor or soft tissue mass should be referred to a pediatric surgeon with experience in oncologic surgery.

For renal tumors, a large transabdominal, transperitoneal incision is recommended for adequate exposure. If the mass is unilateral, a radical nephrectomy with subtotal ureterectomy should be performed. The tumor should be removed en bloc to avoid tumoral spillage into the peritoneal cavity because this spillage increases the stage of the tumor. If the mass involves the upper pole of the kidney, the adrenal gland should be removed.

Lymph nodes from the iliac, para-aortic, and celiac areas should be sampled, even if they do not appear abnormal. Lymph node dissection is not indicated. If the tumor is bilateral or unresectable, biopsy should be performed. If a bilateral or unresectable tumor is diagnosed, preoperative chemotherapy is recommended to shrink the tumor and facilitate subsequent resection. If MRT is diagnosed, complete removal of the tumor is advised.

For extrarenal tumors, the surgical approach depends on the site of disease. Complete resection should be attempted if feasible. If not initially feasible, a preoperative course of chemotherapy is advised.



Therapy for MRT is intensive and requires a multidisciplinary effort.

Practitioners who should be consulted include the following:

  • Pediatric oncologist

  • Pediatric surgeon or urologist

  • Radiation oncologist

  • Pediatric clinical geneticist or genetics counselor

  • Social worker

  • Nutritionist


Diet and Activity


No dietary restrictions are necessary. The patient's nutritional status should be closely monitored to ensure adequate caloric intake during intensive chemotherapy. Parenteral nutrition may be required at some point during treatment.


No restrictions on activity are necessary except during periods of thrombocytopenia. Standard neutropenic precautions should be employed when appropriate.