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High Risk Category

Metastatic rhabdomyosarcoma accounts for approximately 15% of patients and has a poor prognosis with overall survival rates of ~30%.

The COG research study for high risk RMS, ARST0431, has been completed.  This study attempted to improve overall survival by combining intensive multi-agent chemotherapy.

  • Cycles of  vincristine / doxorubicin / cyclophosphamide (VDC) were alternated withifosfamide / etoposide (IE) using interval dose compression.
  • This study included children < 10y with metastatic embryonal RMS, although this group may have slightly better outcomes.Early outcomes appear promising with 18 month FFS and OS rates of 66% and 80% (18 month FFS 20% higher than previous studies).


  • Previous up-front window studies in high risk patients: Identified vincristine/irinotecan andifosfamide/etoposide to be a particularly active combinations with 41% and 70% overall response rates respectively when given prior to VAC.
  • Vincristine and irinotecan (VI) were combined with radiation therapy, as camptothecins have been shown to potentiate effect of RT in an attempt to improve local control.  This is important because at least 50% of treatment failures include the primary site in both intermediate and high risk groups.



  • Patients received RT beginning at Week 20 to the primary tumor and to metastatic sites excepting those with parameningeal tumors with intracranial extension (direct extension into the brain) and those requiring emergency RT (cord compression).
  • Irinotecan and vincristine are given concurrently with RT starting Week 19.

GTV  = Gross Tumor Volume

  • Visible and/or palpable disease prior to any surgical debulking (physical examination, CT, or MR (T1 MR image with contrast is best)
  • Also included enlarged, but unresected, regional lymph nodes.

CTV  = Clinical Target Volume

  • CTV = GTV plus 1 cm (but not extending outside of the patient).  
  • Included regional lymph node chains for clinically or pathologically involved nodes.
  • If no evidence of nodal involvement (N0), the draining regional lymph nodes were not irradiated.
  • For some sites CTV was modified to account for anatomic barriers to tumor spread.
  • For an intraabdominalprimary tumor, if there was a risk of peritoneal dissemination, the CTV was the whole abdomen.

PTV  = Planning Tumor Volume

  • PTV = CTV plus a margin to account for day-to-day setup variation related patient immobilization and physiologic motion (usually 0.5 cm).

RT Dose:

To primary and metastatic sites - for no surgery ever or initial surgery – no second look.

  • Total dose for gross residual disease to all sites except orbit 50.4 Gy
  • Orbit  45 Gy
  • If resected margins negative and alveolar histology 36 Gy
  • If resected margins negative and embryonal histology no RT given
  • After resection if microscopic residual, node negative 36 Gy
  • After resection if microscopic residual, node positive 41.4 Gy
  • All treatments are given in 180 cGy fraction size.

Patients with parameningeal disease have poorer outcomes. Although there is no study evidence, dose escalation could be considered.

To primary and metastatic Sites following Second Look Surgery for both alveolar and embryonal histology

  • If resected and margins negative 36 Gy
  • Microscopic residual, node negative 36 Gy
  • Microscopic residual, node positive 41.4 Gy
  • Gross residual disease 50.4 Gy


Limits on RT dose to spare normal tissues: (180 cGy fraction size)

Bilateral kidneys 

14.4 Gy

Whole liver

23.4 Gy

Bilateral lungs

15 Gy

Optic nerve and chiasm 46.8 Gy
Spinal cord 45 Gy
Gastrointestinal tract 45 Gy
Heart 30.6 Gy
Lens 14.4 Gy
Lachrymal gland/cornea 41.4 Gy

Whole abdomen pelvis

Malignant ascites or peritoneal metastatic lesion

24.0 Gy @ 150 cGy/fraction

  • Volume reduction used for Group IV patients whose total dose was 50.4 Gy.
  • The initial PTV was reduced to the original GTV plus 5 mm after a tumor dose of 36 Gy  (if node negative) or 41.4 Gy (if node positive).
  • Patients with one or more pulmonary metastases or pleural effusion received bilateral whole lung radiation to 15.0 Gy in 150 cGy fractions. If there was gross residual disease, which could be boosted, it was treated to 50.4 Gy, by a shrinking field technique.

A recent study showed that unfavorable histology (alveolar) tumors have a risk of recurrence even in the setting of negative margins of excision.  Radiotherapy would be recommended for most of these patients – but each case should be assessed carefully.

For tumors with no evidence of nodal involvement (N0), the draining regional lymph nodes are not treated with RT.


Metastatic RMS

COG-ARST08P1 is a trial to evaluate the addition of novel therapeutic agents to the intensive chemotherapy used in COG-ARST0431. Newly diagnosed patients with metastatic rhabdomyosarcoma (excluding patients younger than 10 years with embryonal rhabdomyosarcoma) who have an expected failure-free survival of less than 20% are eligible. The study consisted of the non-randomized single-arm pilot studies. Prelimary results are shown below:

  • Pilot 1 assesses the feasibility of  adding cituxtumumab, a fully human IgG1 monoclonal antibody targeting the insulin-like growth factor-I receptor (IGF-IR), to most known effective chemotherapy agents in rhabdomyosarcoma.
  • Pilot 2 assesses the feasibility of adding temozolomide, an alkylating agent, to vincristine/irinotecan cycles, based on the synergistic activity of temozolomide when added to irinotecan.
  • Early results (median follow-up 1.6 years) show 18-month EFS 68% with cituxtumumab and 39% with temozolomide. Overall outcome for metastatic RMS remained poor.



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