4. DISCUSSION
The combined analysis of the results of these two cooperative studies
suggests that different strategies of chemotherapy may have an impact in
the outcome of a subgroup of patients with ARMS and regional nodal
involvement.
The prognosis of patients with ARMS N1 has been reported to be poor in
the historical series of European co-operative studies. In the CWS-86
study, 3-year EFS was 25% and OS 29% [11]. In the SIOP MMT84
study, 5-year EFS was 31% comparable to that of stage IV disease
[16].
The experience of similar patients in North American cooperative groups
has been better than that of the European studies. Of 125 patients with
localized RMS and nodal involvement enrolled in the IRS-IV study,
Rodeberg et al [17] reported 43% five-year failure-free survival of
patients with ARMS and nodal involvement. The overall outcome of
patients with alveolar histology and N1 disease reported in that study
was similar to that of patients with metastatic disease at a single
site.
We recently reported the experience of EpSSG RMS2005 [12] in
patients with ARMS N1 and showed results similar to the IRS-IV study.
The reasons for this apparent improvement in the outcome of these
patients, compared to those treated within previous European studies,
could be due in part to better risk stratification, more adequate
treatment with intensified chemotherapy, systematic local treatment
and/or improvement in supportive care.
Failures among patients reported in the present study were predominantly
with metastatic disease and was similar in both cohorts. Their tumors
frequently presented with advanced IRS Group and unfavorable location,
characteristics related to an increased risk of distant metastatic
disease [18-20]. Local recurrences represented one-third of all
relapses in both protocols and local treatment in RMS2005 and in
ARST0531 was identical. However, Casey et al [21] reported more
loco-regional relapses in patients enrolled in ARST0531 compared with
the previous COG intermediate-risk RMS study, D9803. The reasons for
this increase in local relapses were not clear but may have been related
to changes in cyclophosphamide dosing, changes in RT administration and
fewer surgical procedures.
The most important difference between EpSSG and COG protocols was the
type of chemotherapy. Patients received three different regimens based
on the use of the standard combination (IVA in EpSSG and VAC in COG) to
which was added doxorubicin and 6 months of maintenance chemotherapy
with vinorelbine and cyclophosphamide in the European study or
irinotecan in the North American study. In RMS2005, doses of alkylating
agents included 54 g/m2 of ifosfamide plus 4.5
g/m2 of cyclophosphamide. In contrast, COG patients
received 16.8 g/m2 (VAC) or 8.4 g/m2of cyclophosphamide (VAC/VI). Moreover, patients in EpSSG received
doxorubicin at a total dose of 240 mg/m2. One-half of
the patients in COG received irinotecan. Total duration of chemotherapy
was 42 weeks in COG protocol vs 50 weeks in EpSSG.
There is no evident advantage of adding doxorubicin or irinotecan to the
standard chemotherapy in these patients. Hawkins et al [13] have
previously reported a lack of improvement with the addition of
irinotecan to VAC in the same of group of patients as the present
analysis. The European experience demonstrated that the addition of
doxorubicin to IVA in patients with high-risk disease also failed to
improve outcome when compared to standard chemotherapy [22].
Moreover, previous experiences in Europe demonstrated that the addition
of carboplatin, etoposide, and epirubicin did not improve the outcome
for patients with high-risk disease enrolled in the SIOP MMT-95 study
[8]. In RMS2005, two toxic deaths and one secondary neoplasm
occurred, so that when designing future studies, we consequently should
search for a balance between the total burden of chemotherapy and the
risk of toxicity.
The impact of FOXO1 fusion status in the outcome of patients in
both cohorts showed important differences. In the European study,
fusion-positive tumors had significantly worse EFS as well as a trend
toward inferior OS, while the EFS/OS of patients enrolled in the COG
study was the same whether they had fusion-positive or fusion-negative
tumors. These contradictory results are intriguing. Numerous studies
have reported the impact of fusion status on the outcome of patients
with ARMS [23-25]. However, this impact could be different in
patients with other adverse prognostic factors. For example, in patients
classified as low or intermediate risk in COG studies, the presence ofFOXO1 fusion has a strong impact in prognosis [25,26] while
in patients of high risk with metastatic disease, the clinical
prognostic factors have a stronger impact than the fusion status
[27]. However, these observations do not explain the differences we
observed between our two homogeneous cohorts. In the European study the
EFS of patients with fusion-negative tumors was 73%, similar to that of
patients considered as high risk in the same protocol [22].
We can hypothesize that those patients with fusion-negative tumors
benefit from a more intense chemotherapy. Patients in ARST0531 received
a lower cumulative dose of cyclophosphamide than in previous COG RMS
studies, with a possible negative impact on outcome [13]. In
contrast, patients with ARMS N1 in RMS2005 could have had a benefit from
the addition of maintenance chemotherapy, similar to the results of
high-risk patients [28].
However, our study presents some limitations, such as the relatively
small number of patients with fusion-negative tumors in both cohorts,
and the higher proportion of patients with fusion status unknown in the
EpSSG cohort, which could reduce the precision of the EFS estimations.
In conclusion, there are some lessons learned from the present combined
analysis that should be further explored in the upcoming studies of both
cooperative groups: First, very different treatment strategies in two
concurrent clinical trials generated similar outcomes for patients with
ARMS and regional lymph node involvement. Second, among patients withFOXO1 fusion-negative ARMS and regional lymph node involvement,
the cumulative dose of alkylators and/or maintenance chemotherapy may
influence outcome and, third, a need persists for innovative therapeutic
strategies for those patients with fusion-positive tumors.