European Paediatric Soft Tissue Sarcoma Study Group RMS 2005 - a protocol for non metastatic rhabdomyosarcoma

In The Netherlands yearly 20 children are diagnosed with a rhabdomyosarcoma
(RMS). RMS is the commonest form of soft tissue sarcoma in children and
accounts for approximately 6% of all childhood malignancy. The prognosis of
children with localized rhabdomyosarcoma has improved dramatically since the
introduction of co-ordinated multimodality treatment. Cure rates have improved
from 25% in the early seventies, when combination chemotherapy was first
implemented, to approximately 70% in more recent years.
Approximately 50% of children with RMS have unfavorable prognostic
characteristics. These patients are stratified in the High Risk Group (HRG).
Prognosis of patients in the HRG with current therapy is only 50%. Therefore
new treatment strategies have to be developed to improve the prognosis for this
large subgroup
Standard chemotherapy for the HRG consists of 9 courses of multidrug
chemotherapy, a combination of Iphosfamide, Vincristin and Actinomycin-D (IVA).
High risk patients are eligible for two sequential randomizations:

The first randomisation concerns the addition of Doxorubicin to the first 4
standard IVA chemotherapy courses. This allows intensification of induction
chemotherapy with Doxorubicin, an agent that has shown to be very effective as
single agent in RMS patients (respons rate [RR] of 65% in an up-front window
setting).

The second randomization concerns the addition of maintenance treatment for HRG
patients who are in complete remission after standard treatment (estimated to
be about 80% of patients in the HRG). The concept of maintenance treatment is
based on a German trial for children with metastatic RMS, that showed (in a
center based randomization) that adding maintenance therapy to standard therapy
was more effective than adding high dose chemotherapy with stem cell rescue
(event free survival [EFS] 50% and 20% respectively). The total duration of
maintenance therapy is 6 months. Maintenance therapy encompasses a daily oral
dose of cyclophosphamide (an agent that has proven to be effective in RMS).
Furthermore patients will get weekly gifts of intravenous vinorelbine on a day
care basis. After every third weekly gift of vinorelbine there will be a week
rest, resulting in a total number of 18 doses of vinorelbine. Vinorelbine is a
promissing agent in RMS treatment as it has been shown to have a RR of 30-50%
in heavily pretreated patients.

Both randomizations are part of a Pan-European trial, also encompassing several
non-European countries. The Dutch Childhood Oncology Centers have decided to
include their patients in this European trial (Decision Dutch Childhood
Oncology Group d.d. september 9, 2005).

During the course of the study 2 randomisation questions will be adressed. Both
questions concern patients in the high risk group.

Randomisation question 1: Will the addition of Doxorubicin to the first 4
standard IVA chemotherapy courses lead to a better survival for patients in the
high risk group? (Intensification question).

Randomisation question 2: Will the addition of maintenance treatment for HRG
patients who are in complete remission after standard treatment lead to a
better survival for patients in this group?

Observational study with double randomisation

Randomisation 1: in the intervention group Doxorubicin will be added to the
first 4 standard IVA chemotherapy courses. Per IVA-chemotherapy course a
patient will get 2 gifts of Doxorubicine of 30 mg/m2 each on day 1 and day 2.
Patients in the control group will get standard IVA-chemotherapy courses.

Randomisation 2: The total duration of maintenance therapy is 6 months.
Patients in the intervention group will get maintenance therapy, encompassing a
daily oral dose of cyclophosphamide 25 mg/m2 for a total duration of 24 weeks.
Furthermore patients in the intervention group will get weekly gifts of
intravenous vinorelbine 25 mg/m2. After every third weekly gift of vinorelbine
there will be a week rest, resulting in a total number of 18 doses of
vinorelbine. Patients in the control group will not get maintenance therapy
after standard IVA-chemotherapy.

The IVA-Doxorubicin regimen was piloted and showed a RR of 84% with acceptable
toxicity. Intensifying induction therapy might lead to a higher incidence of
infections or an increase of the need for blood transfusions. Because of this
patients might spend more days in hospital.
The chances for cardiotoxicity adding Doxorubicin in a cumulative dose of 240
mg/m2 are low. Furthermore cardiac function will be monitored according to the
protocol.
Given the relatively poor prognosis of RMS patients in the HRG, the possible
chances for a better prognosis outweigh the low risk for possible negative side
effects.

The combination of Vinorelbine and Cyclophosphamide was piloted in a phase 2
study, was well tolerated, and appeared to have a RR of 38% in heavily
pretreated patients. Maintenance treatment is given on an outpatient basis, and
does not add any important risks for a patient group that might benefit from an
improvement of survival.