Radiol Oncol 2001; 35(4): 259-66. 

Evolving strategies in the treatment of childhood rhabdomyosarcoma: 
Slovenian experience 

Živa Pohar-Marinšek1, Jožica Anžič2, Breta Jereb3 

1Department of Cytopathology, Institute of Oncology, 2Hemato-oncological unit, University 
Children’s Hospital, University Medical Center, 3Institute of Oncology, Ljubljana, Slovenia 

Background. Neoadjuvant chemotherapy (Cht) has changed the treatment of rhabdomyosarcoma (RMS) in 
children. The purpose of our study was to review the children treated for RMS between 1974 and 1996. 
Patients and methods. Fifty-one children, 1-15 years old, were included. Primary sites of tumour were: 
head and neck 15, orbit 6, genitourinary 12, extremity 9, torso 5 and paratesticular 4. Twelve patients were 
in stage I, 10 in stage II, 26 in stage III and 3 in stage IV. Of 43 histologically confirmed RMS 25 were embryonal, 
13 alveolar, 1 botryoid, 1 spindle cell and 3 sarcoma NOS. In 8 patients, only fine needle aspiration 
biopsy (FNAB) was available. All patients had Cht, 29 neoadjuvant, 20 had surgery first, 40 had irradiation 
(RT), 2 stage IV patients had bone marrow transplant (ABMT). Multidrug Cht varied: VCR, AMD, 
and cyclophosphamide (VAC) were used in the 1970s, with Adriablastine (T2), methotrexat (MTX) and/or 
other drugs (T6, T11) in the 1980s, and in the 1990s, cyclophosphamide was replaced by ifosfamide (VAIA). 
The treatment was started with Cht in orbital and head and neck tumours and in the majority of genitourinary 
tumours, but surgery was first in paratesticular and in the majority of extremity tumours. 
Results. The 3 patients with stage IV disease died. Of those with localised tumour, 34 (70%) were alive and 
well 5 years after treatment, 80% stage I, 75% stage II and 61% stage III. One patient died of heart failure, 
3 of Cht toxicity and 1 of intercurrent disease. 
Conclusions. The survival of our patients has improved during the last 2 decades and increased from 57 % 
to 70 % for patients treated after l985. It is now comparable to that in other centres. With the introduction 
of neoadjuvant Cht, surgery and RT have become more conservative and could sometimes even be abandoned, 
thereby reducing considerably the risk of late sequels. Orbital, genitourinary and paratesticular embryonal 
RMS of low stages have very good prognosis. Primary tumours of the extremities and head & neck, 
mainly of alveolar type, have poor prognosis. For alveolar type of RMS and stage IV tumours, the present 
treatment modalities, including ABMT, are not effective. 

Key words: rhabdomyosarcoma – therapy, child, survival analysis 

Correspondence to: Prof. Berta Jereb, MD, PhD, 
Institute of Oncology, 1000 Ljubljana, Zaloška 2,

Received 3 October 2001 

Slovenia; Phone +386 1 522 42 49; Fax +386 1 431 41 
Accepted 20 October 2001 80, E-mail: zpohar@onko-i.si 


Pohar Ž et al. / Childhood rhabdomyosarcoma in Slovenia 

Introduction 

When treating a child with a malignant tumour 
we try to achieve a cure with minimal 
risk for early, as well as late toxic effects of 
treatment.1 This aim is easier to reach in early 
stages of the disease. The cure rate has significantly 
improved in the last decades with 
the introduction of multidrug chemotherapy 
(Cht). This is now used practically in all solid 
malignant tumours in children.2,3 With the 
introduction of neoadjuvant Cht, surgery and 
radiation therapy have acquired more the role 
of adjuvant treatment may be more conservative 
and even be omitted in some cases after 
a complete response to Cht. The advantages 
are twofold: the response of the tumour can 
be evaluated in each particular patient, but 
not only statistically. Therefore, it can continue 
and be successful also after surgery. 
Moreover, Cht can be sufficient as the only 
treatment.4,5 A morphological diagnosis to 
confirm malignancy is required before treatment 
as well as for the choice of proper Cht.6 
The aim of this study was to review the children 
with rhabdomyosarcoma (RMS), treated 
at the Hemato-oncological unit of the 
University Children’s Hospital and at the 
Institute of Oncology in Ljubljana during a 
23-year period. 

Patients and method 

Between l974 and l996, 5l children aged from 
l to l5 years (median 6) and registered at the 
Cancer Registry of Slovenia with the diagnosis 
of RMS, were managed by a team of physicians 
at the Hemato-oncological unit of the 
University Children’s Hospital and the 
Institute of Oncology in Ljubljana. Five children 
with RMS, who were first treated and 
/or followed outside Slovenia, are not included. 
Evaluation of the tumour extent included 
clinical examination, plain radiography computed 
tomography (CT), magnetic resonance 

imaging (MRI), ultrasound, technetium bone 
scan, bone marrow biopsy, spinal tap in patients 
with parameningeal disease and those 
with stage IV tumours. The tumours were 
staged according to the SIOP-UICC7 as fol


lows: 
Stage I: Tumour restricted 
to the organ of origin 12 
Stage II: Tumour invasion 
beyond the organ of origin 10 
Stage III: Tumour with 
regional metastases 26 
Stage IV: Tumour with 
distant metastases. 3 

The following primary sites were defined: 
Head & Neck 15 

Parameningeal 8 

pterigopalatinal fossa 1 

nasopharynx 3 

maxilla 4 
face 5 
ear lobe 1 

oral cavity 1 
Orbit 6 
Genitourinary 12 

vagina 4 

prostate 1 

(para)vesicular 7 
Paratesticular 4 
Extremity 9 

lower 5 

upper 4 
Torso 5 

There were 27 boys and 24 girls less than 
l6 years old at diagnosis (mean 6.9, SD 4,2). 
The diagnosis was provided by fine needle aspiration 
biopsy (FNAB) in 20 and by surgical 
biopsy in 31 patients prior to treatment. Of 43 
histologically confirmed RMS, 25 were embryonal, 
13 alveolar, 1 botryoid, 1 spindle cell 
and 3 sarcoma NOS. Multidrug chemotherapy 
varied. Vincristine, actinomycin D and cyclophosphamide 
(VAC) were used in the 
1970s, VAC in combination with adriablas-

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Pohar Ž et al. / Childhood rhabdomyosarcoma in Slovenia 

Table 1. Chemotherapy according to stage (51 patients) 


CHT/ 
Stage 
VAC T2, VACA 
& VAIA 
T6, T9 & T11 NP* 
I 
II 
III 
IV 
Total 
2 
3 
2 
/ 
7 
6 
5 
10 
/ 
21 
3 
1 
14 
/ 
18 
2 
/ 
/ 
3(ABMT) 
5 

*CIVADIC 

tine (T2 -protocol, VACA) and methotrexate 
(T6 or T11-protocols) in the 1980s. VACA or 
VAIA (cyclophosphamide replaced by ifosfamide) 
were used in the 1990s (Table 1). 

All 5l patients received Cht; 29 neoadjuvant, 
20 had surgery first, in 40, Cht was 
combined with irradiation (RT). Of the 3 
stage IV patients, 2 had bone marrow transplant 
(ABMT) at first treatment and one had 
half body RT in combination with Cht (VAIA 
alternating with VP 16 and cisplatinum) and 
RT to all involved areas. 

The treatment was started with Cht in orbital 
and head and neck and in the majority 
of genitourinary tumours, whereas surgery 
was the first treatment in paratesticular and 
in the majority of extremity tumours. Twenty-
one patients had no surgery (2 stage I, 1 stage 
II, 15 stage III and the 3 stage IV patients). 
Surgery was delayed in 10 patients (5 genitourinary, 
1 orbital recurrence, one extremity 
and one torso) (Table 2). 

Forty patients received RT to primary or 
metastatic site (including the 2 who had 
ABMT). In 2 patients with maxillary primary 
tumours, RT was given at first treatment, 
while in 24 patients, after Cht and in l6 also 
after surgery. The doses of RT varied between 
30 Gy and 50 Gy, depending on tumour stage 
and response to Cht as well as on the experience 
of an earlier study.8 Two patients received 
60 Gy. 

The patients were followed between 5 and 
26 years (median 12) from the diagnosis. 
None were lost from the follow-up. The survival 
was calculated from the date of the diagnosis 
until December 3lst 2000, when the 
study was concluded, or until the date of 
death. It was presented in survival curves according 
to the Kaplan-Meier method.9 The 
statistical significance was calculated using 
the log rank test. 

Results 

Sixty-seven % of all patients included in the 
study and 70 % of those with locoregional disease 
were alive and well more than 5 years 
from diagnosis. The survival of patients treated 
before l985 was 57 % (12/21) and 70 % (21/ 
30) of those treated after 1985. Of the l7 patients 
who died, l3 died of tumour, 4 of complications 
and one, l8 years after diagnosis, of 
an intercurrent disease without tumour. 
Toxicity due to Cht was the cause of death in 

Table 2. Treatment according to primary site (48 patients, stage IV excluded) 

Site 
Ctotal 
hemotherapy 
1th 2nd total 
Surgery 
1th later 
RT* 
total 
Orbit 6 5 1 2 1 1 6 
Head& Neck 13 5 8 6 6 / 13 
Genitourinary 12 7 5 10 5 5 8 
Extremity 7 4 3 6 3 3 6 
Torso 6 5 1 2 1 1 4 
Paratestis 4 / 4 4 4 / / 
Total 48 26 22 30 20 10 37 

*radiotherapy 

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Pohar Ž et al. / Childhood rhabdomyosarcoma in Slovenia 

2 patients treated for recurrence and in one 
stage IV patient. Cardiotoxicity was the cause 
of death in one patient with stage III alveolar 
RMS of the anterior thoracic wall 8 years after 
completed treatment. At the time of 
death, a recurrence was also present. She was 
3 years old at diagnosis. She was treated by 
Cht according to T2 protocol, including adriablastine 
and concomitant RT to the thoracic 
wall (4500 Gy given in split courses during 3 
months). 

The survival of the patients with stage I 
and stage II was very good, while it was significantly 
worse for the patients with stage III 
and stage IV (Figure 1). None of the stage IV 
patients survived, all had multiple bone 
metastases. All patients with orbital tumours 
and those with paratesticular tumours survived. 
Of the l2 patients with genitourinary 
tumours, one with primary tumour of the 
prostate died. Patients with primary tumours 
of the head and neck, torso and extremities 
did poorly. The patients with paratesticular, 
orbital and genitourinary primary tumours 
did significantly better than those with tumours 
of other primary sites (Figure 2). The 
survival was not different in those patients in 
whom treatment was started with Cht com-


PA = paratesticular, OR = orbit, GU = genitourinary, 
TO = torso, EX = extremity 

Figure 2. Disease free survival by tumor site in 48 patients 



pared to those who received Cht postopera-
tively (Figure 3). Furthermore, there was no 
difference in survival between those who had 
no surgery, delayed surgery or surgery as first 
treatment (Figure 4). The outcome of the dis-
Figure 3. Difference in disease free survival between 
patients with adjuvant and neoadjuvant chemothera-
py (48 patients) 
ease in patients who had more intensive Cht 

Figure 1. Disease free survival by stage in 51 patients. 

Radiol Oncol 2001; 35(4): 259-66. 


Pohar Ž et al. / Childhood rhabdomyosarcoma in Slovenia 


Figure 4. Disease free survival by surgery in 48 patients 



Figure 5. Disease free survival by type of chemotherapy 
in 48 patients. 

was not better compared to those who had 
VAC (Figure 5). The morphological type of 
RMS did not significantly influence survival 
(Figure 6). There were two late deaths after recurrence, 
both in patients with alveolar type 
of RMS. 

Discussion 

In our series of patients with RMS the distribution 
of sex, age and primary sites is similar 
to that of other reported studies. The same is 
true for the overall 5-year survival, which has 
improved in Slovenia during the last two 
decades from 57 % to 70 %.10,11 The stage of 
the disease and the site of the primary tumour 
significantly influence the outcome, as 
known. Recently, a staging classification, 
based on the experience of the IRS group, 
was proposed, with some low stage tumours 
classified as unfavourable and some tumours 
of higher stages with expected favourable 
outcome.12 In our experience, this has not 
been entirely confirmed. Patients with primary 
parameningeal tumours, classified as 
unfavourable, regardless of the stage, do extremely 
poorly (only one of the 8 survived) as 
also reported by others. All 7 patients with 
vesicular and paravesicular primary tumours, 
however, are among survivors (Table 3). Only 
2 of them had tumours with less than 5 cm in 
diameter, all embryonal RMS. All patients 
with genitourinary primary tumours, except 
one with a primary tumour of prostate, survived. 


The influence of tumour morphology on 
survival could not be statistically confirmed 
in our small series; however, it was noted that 
the patients with the alveolar type of tumour 
did poorly (Figure 6). This finding is consistent 
with other reports.13,14 Fourteen patients 
had alveolar RMS, including 3 stage IV patients 
and only 5 out of the remaining 11 with 
locoregional disease are among survivors. Of 
the 6 who died, 5 had local recurrence (one 
died of cardiotoxicity with the tumour still 
present). They died 3, 4, 6 and 8 years after 
diagnosis. The results of the IRS studies II 
and III differ regarding the influence of tumour 
morphology on survival. It has therefore 
been suggested that the primary site, correlated 
to the histological type, is the 
prevailing and independent prognostic fac-

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Pohar Ž et al. / Childhood rhabdomyosarcoma in Slovenia 

Table 3. Patients with primary tumours of the bladder or tumours invading the bladder 

Pt I Sex Age in Year of Prim. site Stage Type Surgery RT Cht Late effects 
years diagnosis 
I.P. M 5 1976 paravesicular T2 N1 M0 S TR 48Gy VAC elevated FSH, 
soft tissue 
atrophy, recurrent 
cystitis 
M.P. M 2 1978 bladder TlN0M0 E Cystectomy none VAC stoma, recurrent 
uroinfections 
K.Ž. F 5 1984 paravesicular T2N0M0 E STR 46 T11 soft tissue 
atrophy, 
amenorrhoe 
M.J. F 1.5 1990 paravesicular T2N0M0 E STR none T2 none 
R.U M 7 1993 paravesicular T2N0M0 E STR 30* VACA none 
B.K. M 2 1994 bladder T2N0M0 E none 37.5 VACA none 
A.M. F 2 1995 bladder TlN0M0 E TUR 39** VACA none 

*Hyperfractionation, **Transperineal implant, Ir 192, TR = Total resection with partial cystectomy, TUR 
Transuretral resection, STR Subtotal resection, S = spindle cell RMS, E = embrional RMS, FSH = follicle simulat


ing hormone 


Figure 6. Disease free survival by morphological type 
in 51 patients. (A = Alveolar, E = Embryonal, B = 
Botroyd, S = spindle cell, NOS= RMS not otherwise 
specified) 

tor.15 It might also be possible that the morphology 
of the tumour did not influence the 
outcome significantly because the patients 
with alveolar tumours received more intensive 
Cht. In our series, the primary site and 
the type of the tumour were correlated (Table 
4). All tumours of the extremities were of the 

Table 4. Primary site versus morphological type 

Primary site Alveolar Embryonal 
and other 
Orbit 1 5 
Head & neck 6 9 
Genitourinary 0 16 
Paratestis 0 4 
Extremity 5 0 
Torso 2 3 
Total 14 37 

alveolar type and all genitourinary and paratesticular 
tumours were of nonalveolar type. 

The survival of patients in our study was 
not influenced by different schedules of Cht 
(Figure 5), which was probably too aggressive 
for some groups of patients. At least 3-drug 
combinations were used, often 4 or even 
more. ABMT has not been reported as successful 
in patients with RMS,16 which was also 
true in our 3 stage IV patients who all had 
bone metastases. 

The group of patients with bladder and 
paravesicular tumours, presented in Table 3, 
reflects the development of treatment approaches 
during the two decades, for the entire 
series. Radical surgery and high dose RT 

Radiol Oncol 2001; 35(4): 259-66. 


Pohar Ž et al. / Childhood rhabdomyosarcoma in Slovenia 

were applied in the 1970s and very aggressive 
and Cht with more conservative surgery and 
lower doses of RT in the 1980s. Later, surgery 
and RT were more conservative, while 4-drug 
Cht was still used. With equal results in 
terms of survival, the consequences of treatment 
are considerably reduced. 

The survival curves for those patients who 
were first treated with surgery and those who 
had neoadjuvant Cht and delayed, more conservative 
surgery are identical (Figure 6). The 
patients who had no surgery at all did not do 
significantly worse, even with the inclusion 
of the patients with high-risk parameningeal 
tumours. 

Conclusions 

During the period under investigation, the 
methods of treatment of children with RMS 
have evolved. With the introduction of 
neoadjuvant Cht, surgery and RT have become 
more conservative or were even abandoned, 
thereby reducing the risk of late sequelae. 
The survival of our children with 
RMS has improved during the period under 
investigation and is now comparable to that 
in other centers. Orbital, genitourinary and 
paratesticular embryonal RMS of low stages 
have very good prognosis and may be cured 
with conservative treatment and less toxic 
chemotherapy. Primary tumours of the extremities 
and head and neck, mainly of alveolar 
type, have poor prognosis with present 
treatment modalities. Hopefully, new Cht 
schedules, will prove more effective. For alveolar 
type of RMS and stage IV tumours the 
present treatment modalities, including 
ABMT, are not effective; therefore, new approaches 
should be considered.17 

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