The current low risk COG research study ARST0331 for embryonal RMS attempts to maximize long-term failure-free survival and minimize short and long-term toxicity, particularly infertility and secondary malignancy related to cyclophosphamide exposure.
There are four initial courses of cyclophosphamide given every 3 weeks, using a dose of 1.2 g/m2/per course (total dose, 4.8 g/m2), with vincristine, and dactinomycin, followed by RT at week 13 for patients with microscopic, locoregional, or gross residual tumor.
Subsequently, two subsets (A and B) have been defined within the low risk category (see risk category page), both with excellent overall survival on IRS-III and IV studies (~95%). Patients receive four (Stratum I) or 12 (Stratum II) further courses of VA, depending on the tumor stage and Group.
Stratum I closed to patient accrual in August 2010.
In ARST 0331, a lower dose of cyclophosphamide (4.8 g/m2 total cumulative dose) is given with vincristine plus dactinomycin and radiation therapy (RT) to areas of residual tumor to patients in each of the two subsets. The duration of therapy is 22 weeks for patients in Subset A and 46 weeks in Subset B.
The protocol is designed to increase efficacy of treatment while shortening the duration of treatment for a subset of low-risk patients and reducing both acute toxicity (myelosuppression) and long-term toxicity (impaired fertility) from cyclophosphamide.
Embryonal/ Botryoid/ Spindle cell Tumors
Stage 1, Clinical Group I |
No radiation therapy (RT) |
Stage 1, Clinical Group II N0 |
Conventional RT - 36 Gy |
Stage 1, Clinical Group II, N1 |
Conventional RT – 41.4 Gy |
Stage 1, Clinical Group III |
Conventional RT – 45 Gy (orbit only) |
Stage 1, Clinical Group III |
Conventional RT– 50.4 Gy (non-orbit) |
Stage 2, Clinical Group I |
No RT |
Stage 2, Clinical Group II, N0 |
Conventional RT - 36 Gy |
Stage 3, Clinical Group I |
No RT |
Stage 3, Clinical Group II, N0 |
Conventional RT - 36 Gy |
Stage 3, Clinical Group II, N1 |
Conventional RT – 41.4 Gy |
All RT is given in 180 cGy fractions.
RADIOTHERAPY
GTV = Gross tumor volume
- Pre-treatment visible and/or palpable disease
- Determined by physical examination, operative surgical findings, CT or MR (T1 sequence).
- This includes any clinically involved lymph nodes. Initial GTV does not change based on any surgical resection or chemotherapy response.
CTV = Clinical Target Volume
- CTV = GTV + 1.0 cm (but not extending outside of the patient).
- For some sites, the definition of CTV is modified to account for specific anatomic barriers to tumor spread.
- CTV will always include the entire draining lymph nodes chain if the regional nodes are clinically or pathologically involved with tumor.
NB. Patients with Clinical Group III disease who do not have a second look operation may have a second CTV and PTV defined for a “cone down”boost.
- These patients will receive a total dose of 50.4 Gy.
- However, if they have a radiographic response to induction chemotherapy, then a cone down boost will be given after a dose of 36.0 Gy.
- This boost volume will be defined as having a CTV of the original GTV at the time of diagnosis plus a margin of 0.5 cm.
PTV = Planning Target Volume
- PTV = CTV plus an institution specific margin to account for day to day setup variation ( depends on ability to immobilize the patient and physiologic motion).
- For many patients, this margin will be 5 mm.
- For patients who are to receive a cone down boost a second PTV will be defined after a dose of 36.0 Gy, based upon the cone down
- The biopsy site and surgical scar should always be included in the RT volume.
- Nodal areas are irradiated if they are clinically positive or biopsy positive. Prophylactic nodal RT for uninvolved nodes (NO) is not advised.
- RT usually starts at week 13.
- Vincristine chemotherapy is given concurrent with RT. Dactinomycin is given at week 13 just before starting RT, but is withheld during RT.
- The prescription point for the PTV is at or near the center of the volume.
- For multi-convergent beams, the prescription point is at the intersection of the beam axes' isocenter.
- All patients with gross residual disease (Clinical Group III) in a favorable site (Stage 1), except most patients with orbital , should be reassessed for a second-look operation and attempt at resection at week 13 if possible.
- All patients with initial nodal involvement (N1) must receive RT regardless of response to induction therapy and second look operation. RT dose to gross nodal disease after initial resection is 5040 cGy. This may be reduced to 4140 cGy if there is only microscopic residual.
