Trial Information

MMT 95 Study For Rhabdomyosarcoma and Other Malignant Soft Tissue Tumors of Childhood

OBJECTIVES:

- Assess whether good survival rates can be maintained for patients with stage I
(pathologic T1) soft tissue sarcomas (STS) treated with limited chemotherapy after
complete surgical resection, and whether disease-free survival can be improved by
improving the precision of pretreatment staging and the assessment of the completeness
of the resection.

- Compare the survival of patients with high-risk nonmetastatic STS treated with
alternating regimens of carboplatin, epirubicin, and vincristine (CEV) and ifosfamide,
vincristine, and etoposide (IVE) vs continuation of ifosfamide, vincristine, and
dactinomycin (IVA) after initial therapy with IVA.

- Assess whether the improved outcome seen for patients with stage III (node positive)
STS in an earlier protocol (SIOP-MMT-89) can be maintained with 3 courses of
alternating CEV/IVE without altering local therapy.

- Compare outcome of patients with nonmetastatic STS to those with stage IV STS who are
registered on this protocol but referred to treatment on the European Intergroup Stage
IV Study.

- Assess survival and the risk of late sequelae in patients with non-rhabdomyosarcoma
malignant mesenchymal tumors treated on this protocol.

- Evaluate the role of neoadjuvant chemotherapy, new prognostic factors (e.g., ploidy,
histologic grading), and recommendations for the management of fibrosarcoma in infants
and of fibromatoses.

- Assess ifosfamide nephrotoxicity based on total dose administered and the long-term
toxicity based on the potential predictive value of early evidence of nephrotoxicity.

OUTLINE: This is a randomized study for patients with high-risk, nonmetastatic sarcoma,
except those with the following characteristics: age less than 6 months, stage I/II
non-alveolar orbital tumor, stage III disease, or age less than 3 years with parameningeal
disease. Patients are stratified according to disease type (rhabdomyosarcoma (RMS) vs
non-RMS disease), parameningeal site of disease, and participating center. Patients with RMS
are further randomized by alveolar histology. Randomization occurs after the first course of
chemotherapy.

All patients, regardless of disease stage, are registered to this study and outcome is
followed, although patients with metastatic RMS or non-RMS malignant mesenchymal tumors are
referred for treatment on the SIOP-MMT-98 study. Patients diagnosed more than 8 weeks prior
to entry or who are unavailable for follow-up are not treated on study. Doses are modified
for patients under 1 year of age or under 10 kg of body weight. All other patients are
assigned therapy based on risk group.

After surgery, patients with complete resection and with proven or possible chemosensitive
histologies proceed to chemotherapy on the low-risk regimen. Patients with questionable
completeness of resection proceed to chemotherapy for standard-risk or high-risk tumors, as
appropriate. Regardless of resection results, patients who underwent scrotal surgery for
paratesticular tumors proceed to chemotherapy for standard-risk tumors. Alveolar RMS is
considered high risk.

LOW-RISK TUMORS (T1 N0 M0): Strategy 951

- Tumors must be resectable without extensive, mutilating surgery, and resection margins
must be microscopically negative at all sites. Patients with positive margins may
undergo re-excision.

- Vincristine is administered weekly for 4 weeks with dactinomycin given on the same day
as the first and fourth doses of vincristine. The course is repeated once after a
3-week rest.

STANDARD-RISK TUMORS (T1-2 N0 M0): Strategy 952

- After resection as above, patients with incompletely resected T1 tumors, completely
resected T1 tumors that extended beyond the tissue or organ of origin, or completely or
incompletely resected T2 tumors at favorable sites (vagina, uterus, or paratesticular
region) receive chemotherapy on this regimen.

- Ifosfamide, vincristine, and dactinomycin (IVA) is started within 8 weeks of surgery
and administered every 3 weeks for 3 courses; during this course only, vincristine is
administered weekly throughout the 6 weeks. Response is assessed at week 8.

- Patients with at least a 50% response at week 8 receive 3 more courses of IVA and are
reassessed at week 17; those with a complete response (CR) discontinue treatment, while
those with less than a CR begin local therapy (described below) on week 18 concurrently
with 3 more courses of IVA (unless no further response was seen after week 8).

- Patients with less than a 50% response at week 8 receive carboplatin, epirubicin, and
vincristine (CEV) on weeks 9, 15, and 21 and ifosfamide, vincristine, and etoposide
(IVE) on weeks 12, 18, and 24. Patients with less than a CR at week 17 receive
concurrent local therapy beginning at week 18.

HIGH-RISK TUMORS: Strategy 953

- Patients with high-risk tumors after surgery are randomized to IVA as in strategy 952
(Arm I) or to 3 weeks of IVA (1 course) as in Strategy 952 followed by CEV and IVE as
in Strategy 952 (Arm II). Response is assessed at week 8. Patients with parameningeal
disease who are at least 3 years of age proceed to radiotherapy at week 9, regardless
of response.

- Patients on Arm I with at least a 50% response at week 8 receive 3 more courses of IVA
and are reassessed at week 17; those who continue to respond between weeks 8 and 17
receive 3 additional courses of IVA. Patients with no further response receive 4
alternating courses of CEV and IVE. All patients with less than a CR at week 17 begin
local therapy on week 18 concurrently with the additional chemotherapy. Patients on Arm
I with less than a 50% response at week 8 receive alternating CEV and IVE as in
Strategy 952. Patients with less than a CR at week 17 begin concurrent local therapy at
week 18.

- Patients on Arm II who have at least a 50% response at week 8 continue treatment with 2
courses of sequential IVA, CEV, and IVE. Local therapy is concurrently administered,
beginning on week 18, to patients who have not achieved a CR by week 17. Patients on
Arm II who have less than a 50% response at week 8 proceed immediately to local therapy
with additional chemotherapy at the investigator's discretion. Patients with less than
a CR after local therapy are considered for treatment on a phase II protocol.

LOCAL THERAPY

- Local therapy consists of conservative resection of residual disease (unless more
debilitating surgery is appropriate). Patients with residual disease after surgery
undergo external-beam radiotherapy 5 days per week for 6-7 weeks or brachytherapy;
hyperfractionation is specifically excluded. For patients receiving radiotherapy, the
dactinomycin dose in the IVA regimen is omitted from the middle course of chemotherapy
and possibly the last course of chemotherapy during concurrent administration. Patients
receiving alternating CEV and IVE have the courses reversed during concurrent
radiotherapy, with possible omission of epirubicin for the third course.

- Radical surgery is considered for any patient who has residual disease at week 27.

TREATMENT FOR RELAPSE

- Patients treated with Strategy 951 proceed to therapy with at least 6 alternating
courses of IVE and CEV, with local therapy initiated after the second course. Other
patients receive at least 6 alternating courses of CEV and vincristine, carboplatin,
and etoposide (modified Vincaepi), with local therapy initiated after the second
course. Patients who have already received either regimen may be re-treated with
carboplatin and etoposide and vincristine and cyclophosphamide if relapse occurs more
than 6 months after treatment, while those who relapse in less than 6 months are
considered for phase II chemotherapy trials. Patients with metastatic relapse are
evaluated for bone marrow or peripheral blood stem cell transplantation.

Patients are followed every 2 months until 2 years after diagnosis, every 3 months for 1
year, every 6 months for 2 years, and then annually until 10 years after diagnosis.

PROJECTED ACCRUAL: A total of 400 patients with high-risk nonmetastatic disease will be
accrued for this study within approximately 4 years.