Patients with localized, grossly resected or gross residual (orbital only) embryonal rhabdomyosarcoma had good outcomes in the IRS protocols. Subsequent studies aimed to maintain outcomes while reducing toxicity in this patient group.
In D9602, radiotherapy doses were reduced and cyclophosphamide was eliminated in the lowest risk patients.
- Subgroup A patients (lowest risk, stage 1, group I/IIA, stage I group III orbit, and stage 2 group I) received vincristine and dactinomycin (VA).
- Subgroup B patients (stage 1 group IIB/C, stage 1 group III non-orbit, stage 2 group II, stage 3 group I/II) received VA plus cyclophosphamide.
- Patients in groups II/III received RT at a reduced dose compared with IRS-IV (table below).
- 5 year failure free survival (FFS) rates were 89% for subgroup A, and 85% for subgroup B patients
- 5 year FFS was 81% for patients with stage 1 group IIA tumors and 86% for patients with group III orbit tumors
In ARST0331, treatment duration was shortened from 45 to 22 weeks, with the addition of low-dose cyclophosphamide for subset one (similar to subgroup A in D9602 but also includes patients with stage 1 group IIB/C and stage II group II) patients. This was a prospective, nonrandomized, noninferiority trial, with results compared with those of similar patients from D9602. This study attempted to maximize long-term failure-free survival and minimize short-term (myelosuppresion) and long-term toxicity, particularly infertility and secondary malignancy.
- Patients in subset 1 received four cycles of VAC (total cumulative cyclophosphamide dose 4.8 g/m2) followed by 4 cycles of VA. RT began at week 13 for patients with group II/III tumors. The dose of cyclophosphamide was selected to preserve fertility in most patients. 3 year FFS was 89% (compared to 3 year FFS 0f 90% in D9602) and 3 year OS was 98%. The impact of cyclophosphamide in this group in unclear.
- Patients with group IIA tumors had improved local control compared with D9602, supporting a role for cyclophosphamide in patients with microscopic residual disease (local failure 8.1% in ARST0331 compared with 11.7% in D9602).
- Patients with group III orbit tumors had similar local control in ARST0331 (11.5%) and D9602 (11.9%)
- Overall, 3 year local failure rates in ARST0331 were higher than in IRS-IV (group IIA 8.1% in ARST0331 vs 2% in IRS-IV; group III orbit 11.5% in ARST0331 vs 4% in IS-IV).
Overall D9602 and ARST0331 support lower radiotherapy doses for patients with microscopic residual disease or gross disease in the orbit, and lower treatment times for patients with low risk embryonal rhabdomyosarcoma.
RT dose |
IRS-IV |
D9602 and |
Group I |
0 |
0 |
Stage 1 group IIA |
41.4 Gy |
36 Gy |
Group III orbit |
50-59Gy |
45 Gy |
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.
Links:
Suman Malempati, MD1,* and Douglas S. Hawkins, MD2
