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T r e a t m e n t o f O r b i t a l R h a b d o m y o s a r c o m a : S u r v i v a l a n dL a t e E f f e ct s o f T r e at m e nt Re s u l ts o f a n I n t e rn a t io n al

W o r k s h o p

By Odile Oberlin, Annie Rey, James Anderson, Modesto Carli, R. Beverley Raney, Joern Treuner,

and Michael C.G. Stevens for the International Society of Paediatric Oncology Sarcoma Committee, the IntergroupRhabdomyosarcoma Study Group, the Italian Cooperative Soft Tissue Sarcoma Group, and the German Collaborative Soft

Tissue Sarcoma Group

Purpose: Orbital rhabdomyosarcoma (RMS) histori-cally has been associated with an excellent survivalrate. The majority of patients are cured with the useof both chemotherapy and radiation therapy, but asignificant number experience important late se-quelae of treatment. In an attempt to determine opti-mal therapy in relation both to cure and to sequelae,the experience of the four international collaborativegroups (Intergroup Rhabdomyosarcoma Study Group

[IRSG], International Society of Paediatric Oncology[SIOP] Sarcoma Committee, German CollaborativeSoft Tissue Sarcoma Group [CWS], and Italian Coop-erative Soft Tissue Sarcoma Group [ICG] studies) wasshared at an international workshop.

Patients and Methods: A total of 306 eligible pa-tients were identified from group records (186 fromIRS, 43 from SIOP MMT, 40 from CWS, and 37 fromICG). Median age was 6.8 years, and median fol-low-up was 6.5 years. Eighty percent of patientsreceived radiation therapy (RT) as part of primarytherapy, but there were significant differences in theuse of RT between the individual groups (93% in IRSG,

76% in ICG, and 70% in CWS, but only 37% in theSIOP MMT group).

Results: At 10 years, event-free and overall survivalfor the whole cohort were 77% (range, 71% to 81%)and 87% (range, 82% to 92%), respectively. There wasno difference in overall survival between the collabo-rative groups regardless of differences in the use ofinitial RT. In total, 34 (12%) of 273 survivors had notreceived RT, although this varied between the different

groups(41% in the SIOPMMT group, 20% inCWS, 7% inICG, and 6% in IRSG). There was no difference in overallsurvival for the whole cohort regardless of whetherradiotherapy was used as part of initial therapy (86%at 10 years for both).

Conclusion: These data suggest that a subset of pa-tients with orbital RMS can be cured without systematiclocal therapy, although the total burden of treatment(primary therapy and treatment for relapse) must betaken into account when assessing the implications forlate sequelae.

J Clin Oncol 19:197-204. 2001 by AmericanSociety of Clinical Oncology.

R HABDOMYOSARCOMA (RMS), the most commonof the pediatric soft tissue sarcomas, arises in amultiplicity of sites. Forty percent, however, originate from

the head and neck region, and 10% develop within the orbit.

In the majority of published series, the orbit is the most

favorable site, with a 5-year survival rate greater than

85%.1-3

The approach to treatment has undergone radical change

over the last 20 years and has evolved from primary exenter-

ation to a more conservative multidisciplinary approach com-

bining systemic chemotherapy and local radiation therapy. The

excellent survival of this group of children has allowed clinical

investigators to follow survivors for many years and, unfortu-

nately, to observe the development of important late effects

resulting from local treatment.4 Problems include both func-

tional and structural changes: cataract and changes in the

cornea and the retina are amongst the most common problems,

but bony hypoplasia of the orbit and facial asymmetry are also

frequently described.

Knowledge of such late effects has led to attempts to

avoid systematic local therapy (almost exclusively given as

radiotherapy) in those patients in whom complete remission

is achieved with primary chemotherapy. This has largely

been explored by the studies promoted by the International

Society of Pediatric Oncology (SIOP) group.5 The chal-

lenge must always be to maintain excellent survival while

demonstrating a reduction in late effects of therapy. Studies

from other collaborative groups, including the North Amer-

ican Intergroup Rhabdomyosarcoma Study Group (IRSG),

From the Institut Gustave-Roussy, Villejuif, France; University of

Nebraska Medical Center, Omaha, Nebraska; University Hospital ofPadova, Padova, Italy; M.D. Anderson Cancer Center, Houston, TX;

Olga Hospital, Stuttgart, Germany; and The Childrens Hospital,

Birmingham, United Kingdom.

Submitted February 17, 2000; accepted August 2, 2000.

Supported in part by Association de Recherche Contre le Cancer,

Villejuif, France (grant no. 1381).

Address reprint requests to O. Oberlin, MD, Department of Paedi-

atric Oncology, Institut Gustave-Roussy, 94805 Villejuif Cedex,

France; email [email protected].

2001 by American Society of Clinical Oncology.

0732-183X/01/1901-197

197Journal of Clinical Oncology,Vol 19, No 1 (January 1), 2001: pp 197-204Downloaded from jco.ascopubs.org on January 30, 2014. For personal use only. No other uses without permission.

Copyright 2001 American Society of Clinical Oncology. All rights reserved.

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the German Collaborative Soft Tissue Sarcoma Group

(CWS), and the Italian Cooperative Soft Tissue Sarcoma

Group (ICG), have been based on protocols that have

generally included chemotherapy and orbital radiation ther-

apy for all patients.

Because of such significant differences in treatment

philosophy, and in an attempt to determine the optimal

balance between a high cure rate and a low risk of

significant late effects from therapy, a workshop was held in

1997 to assess the treatment of orbital RMS and its outcome

between the four international groups contributing data.

Representatives from the IRSG, CWS, ICG, and SIOP all

participated. Data from the different treatment protocols

were pooled to undertake an analysis of prognostic factors

in a large cohort of children with nonmetastatic orbital

RMS.

The primary purpose of the workshop was to explore the

impact of radiotherapy on ultimate survival when given as

part of primary treatment and to assess, where possible, the

extent to which local treatments contributed to significant

late effects of therapy.

PATIENTS AND METHODS

Patient Population

Analyses were performed on the data derived from nine studies from

the four cooperative groups (IRS II, IRS III, IRS IV, CWS 81, CWS 86,

ICG 79, ICG 88, SIOP MMT 84, and SIOP MMT 89). The overall

study population consisted of 306 children with nonmetastatic RMS of

the orbit treated between 1979 and 1992. Patients with parameningeal

extension of their tumor, regional nodal involvement, or metastaticdisease were all excluded from the analysis. All patients had received

histologic confirmation of tumor and all were more than 2 years beyond

the date of last treatment. Arrangements for central pathology review

existed within each collaborative group structure and diagnoses were

not specifically rereviewed for this study. Furthermore, the span of

years of diagnosis for the patients in this study implied that differences

in diagnostic criteria and staging technology will have evolved both

within and between the contributing groups. It is possible that these

differences may contribute to effects otherwise attributed to differences

in treatment strategy.

Treatment

All patients received multiagent chemotherapy, but major differ-

ences in philosophy and practice were observed with regard to the useof radiation therapy.

IRSG Studies. In the IRS II study (84 patients), children with

microscopic residual disease were randomized to receive either a

two-drug regimen (vincristine and dactinomycin [VA]) or a three-drug

regimen (vincristine, dactinomycin, and cyclophosphamide [VAC]);

children with gross residual disease after surgery (usually after initial

biopsy only) were randomized to receive either VAC chemotherapy or

VAC plus doxorubicin. All patients were scheduled to start irradiation

at week 6: the prescribed dose was 41.4 Gy for patients with

microscopically positive margins and 45 to 55 Gy for those with gross

residual disease, depending on age and on the size of the primary tumor

before initiation of chemotherapy. Dactinomycin and doxorubicin

were omitted during radiation. The total duration of chemotherapy

was 2 years.

In the IRS III protocol, all patients (n 102) received VA for 1 year

with radiation therapy beginning at week 2. Patients with completely

resected tumor were not given radiotherapy, and patients whose tumorswere not removed completely were given radiation at doses defined as

in IRS II.

In the IRS IV study, patients (n 20) were randomized to receive

either VAC; vincristine, dactinomycin, and ifosfamide (VAI); or

vincristine, ifosfamide, and etoposide (VIE) for 1 year. Radiation

therapy was given from week 9. The radiotherapy schedule was

randomized between 50.4 Gy in a conventional daily schedule or

59.4 Gy in a hyperfractionated schedule. A single patient with a

completely removed tumor received only VA chemotherapy without

radiation therapy.

CWS Studies. In the CWS 81 study (14 patients), chemotherapy

was given as vincristine, dactinomycin, cyclophosphamide, and doxo-

rubicin (VACA) for a 35-week period. Radiation dose was stratified

depending on the outcome of second-look surgery: patients who did not

undergo second-look surgery or who had macroscopic residue were

given 50 Gy, and patients with microscopic residue received 40 Gy, all

by conventional fractionation.

In the CWS 86 study (28 patients), the chemotherapy combination

was changed by replacing cyclophosphamide with ifosfamide (VAIA).

The radiation dose was determined according to chemotherapy re-

sponse derived by the degree of tumor volume reduction (32 Gy if

regression was two thirds of the initial volume and 54.4 Gy in all

other patients).

ICG Studies. In ICG 79, patients (n 25) were randomized to

receive either VAC or modified VAC (VACM

).6 Radiation therapy was

scheduled at weeks 13 to 14 and dose was defined according to

chemotherapy response or the result of second-look surgery, if per-

formed. The dose given was 40 to 45 Gy in patients with microscopic

residual disease and 50 to 55 Gy in those with gross residual disease,depending on age and tumor size at diagnosis. Initially, patients with

orbital tumors achieving complete clinical remission with primary

chemotherapy were not intended to receive radiation therapy, but the

protocol was amended after the occurrence of three local relapses in the

first four children treated. Treatment continued with alternate courses

of VACM

and cyclophosphamide, doxorubicin, and vincristine (CAV)

for a total of 12 to 18 months.

In the ICG 88 study, patients (n 16) received the VAIA regimen

as initial chemotherapy and the VAI regimen as subsequent treatment

for a total of 6 to 8 months. Radiation therapy was scheduled at week

11 and given in an accelerated hyperfractionated schedule at a dose of

40 to 54.4 Gy according to chemotherapy response. Radiation therapy was

not given to patients with histologically confirmed complete remission.

SIOP Studies. Patients in the SIOP 84 study (n

20) receivedchemotherapy consisting of ifosfamide, vincristine, and dactinomycin

(IVA) followed by second-line chemotherapy with doxorubicin and

cisplatin in cases of partial response or progressive disease. In the SIOP

89 study (n 24), the same initial chemotherapy combination was used

but second-line chemotherapy consisted of vincristine, teniposide/

etoposide, and carboplatin (Vincaepi). The total duration of chemother-

apy was 3 to 6 months according to stage. In neither study did patients

who achieved complete remission with chemotherapy alone receive

radiation therapy as part of first-line therapy. Those who had residual

macroscopic or histologically proven microscopic disease received

radiation therapy at a dose of 45 Gy by conventional fractionation.

198 OBERLIN ET AL

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Table1.

PatientC

haracteristicsAccordingtoCollaborativeGroup

Total

IRSG

CWS

ICG

S

IOP

No.

of

Patients

%

No.of

Patients

%

No.of

Patients

%

No.of

Patients

%

No.of

Patients

%

No.ofpatients

306

186

40

37

43

Periodofaccrual,year

1978-1992

1978-1992

1981-1990

1980-1992

1984-1992

Study,no.ofpatients

IRSII:841

CWS81:14

ICG79:25

MMT84:20

IRSIII:102

CWS86:28

ICG88:16

MMT89:24

IRSIV:20

Follow-upofsurvivors,months

Median

82

82

91

116

86

Range

25-204

25-204

40-159

50-189

39-145

Ageatdiagnosis,years

Median

6.8

6.5

6.7

7.9

6.1

Range

1-17

1-16

1-17

1-17

1-14

Agedistribution

3years

50

16

30

16

7

18

3

8

10

23

3-7years

130

85

14

14

17

7years

126

71

19

20

16

Sex M

ale

157

51

90

48

20

50

21

57

26

60

Male:female

1.0

5

0.9

4

1.0

1.3

1

1.5

3

Primarytumor

Orbit

271

89

179

96

35

88

33

89

25

58

Eyelid

19

7

3

3

6

Both

15

2

1

12

Localextension

T1

84

70

NA

32

80

30

81

22

51

T2

36

8

7

21

Size

5cm

219

91

112

89

35

92

34

94

38

95

5cm

21

14

3

2

2

Unknown

66

60

2

1

3

Histology

EmbryonalRMS

267

87

172

92

32

80

30

81

33

77

Embryonalsarcoma

10

13

4

10

6

14

AlveolarRMS

29

10

14

8

4

10

7

19

4

9

Initialsurgery*

Completeremoval

9

3

3

3

2

1

Microscopicresidue

38

12

16

8

8

6

Macroscopicresidue

37

12

14

8

10

5

Biopsyalone

222

73

153

82

21

52

17

46

31

73

Abbreviations:T1,

Tumorlocalized

totheorganortissueoforigin;T2,

Tumorextend

ingbeyondthetissueoforigintoinvolveoneor

moreadjacenttissues;NA,notavailable.

*Noenucleationorexenterationwa

scarriedoutaspartofinitialsurgery.

199TREATMENT OF ORBITAL RHABDOMYOSARCOMA


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Statistical Analysis

Statistical analyses were performed at the Institut Gustave Roussy in

Villejuif, France, using a general database management system. Sur-

vival curves were calculated by the method of Kaplan-Meier.7 Survival

was calculated from the date of the start of treatment to the time of the

last follow-up or death. Event-free survival (EFS) was calculated from

the date of the start of treatment to the date of the first event, such as

failure to achieve complete remission, relapse, or death from any cause.

Local control was defined as disappearance of all clinical and radio-

logic signs of disease or as stable residual radiographic images for 6

months after completion of treatment. The date of analysis was May

1997, providing a minimum of 4 years from the last date of study entry.

The statistical significance of each variable was tested in a univariate

analysis using the log-rank test.8

RESULTS

Patient Characteristics

The initial characteristics of the 306 patients are pre-sented in Table 1. The median age at diagnosis was 6.8

years, with a range of less than 1 year to 17 years; 50

patients (16%) were younger than 3 years (IRS 16%,

CWS 18%, ICG 8%, and SIOP 23%). Male patients

represented 51% of the population. Median follow-up of

survivors was 82 months, with a range of 25 to 204 months.

Details of stage, size, site, histology, and initial surgery are

listed in Table 1.

Primary Treatment

Overall, 72% (n 222) of patients underwent initial

biopsy only and had tumors that were considered unresect-able at diagnosis, although there was an apparent difference

in surgical practice between the different groups, with the

percentage of patients starting therapy after biopsy only

varying from 82% (IRSG) to 46% (ICG). A partial excision

was achieved by initial surgery in 75 patients (25%), but

only nine patients (3%) had a successful initial complete

excision (Table 1).

The details of radiotherapy are given in Table 2. Alto-

gether, 245 patients (80%) were irradiated, but this propor-

tion varied significantly between the different groups. In

those treated in the SIOP studies, only 16 (37%) were

irradiated, all after failure of initial chemotherapy to achievecomplete remission. Radiation therapy was withheld in the

ICG 88 study only in those with histologically confirmed

complete remission, and in all other studies initial irradia-

tion was planned for every patient, although not all actually

received it. Overall, 178 patients (93%) in the IRS studies,

28 patients (70%) in the CWS studies, and 28 patients

(76%) in the ICG studies received radiation therapy. Among

the irradiated cohort, 33 (13%) were younger than 3 years of

age (IRS, 16%; CWS, 8%; ICG, 8%; SIOP, 13%).

Remission, Survival, and Relapse

Complete remission was achieved in 294 patients (96%).

Recurrence occurred in 51 patients (17%). Median time to

relapse was 18 months, with only two relapses occurring

beyond 5 years from diagnosis. Among the 51 patients whorelapsed, 47 (92%) experienced a local relapse (including

three patients with local plus distant relapse). Only four

patients (8%) developed distant metastases (Table 3).

Among the 47 local recurrences, 27 occurred in nonirra-

diated patients (27 of 61; 44%) and 20 occurred after

radiotherapy (20 of 245; 8%). The median radiation dose

received by the patients who relapse after radiation was not

different from the median dose given to those who did not.

The rate of local relapse varied between the IRSG and

European studies (5% in IRS, 30% in CWS, 35% in ICG,

and 36% in SIOP).

At the time of analysis, the median follow-up of survivorswas 7 years. The 10-year actuarial EFS was 77% (range,

71% to 81%) for all patients. Figure 1 shows EFS according

to the different treatment groups. This was significantly

better for children in the IRS study than for those in the

three other studies (P .001). The 10-year actuarial overall

survival (OS) was 87% (range, 82% to 92%) for the whole

cohort of patients. Figure 2 shows OS according to the

different treatment groups. There was no difference in

survival between groups. Figure 3 shows the EFS according

to the use of radiotherapy as part of primary treatment and

Fig 4 shows the similar analysis for OS. It can be seen that

initial radiation therapy has impact on EFS but no impact onOS.

Table 3 gives the status of patients at the time of last

contact. A total of 273 patients were alive, of whom 238

were in first remission and 26 were in subsequent remission

after relapse; nine were alive with disease. In total, 33

patients had died, of whom seven never achieved complete

remission, 21 died after relapse, and four died from treat-

ment-related causes (two with sepsis and two from anthra-

cycline-related cardiomyopathy). The cause of death was

unknown in one patient.

Burden of Therapy in Surviving Patients

Within the IRS group studies, 91% of the surviving

patients had received radiation therapy during initial treat-

ment, but data relating to treatment received for relapse

were not available. For the children included in the three

European group studies, data were available both for initial

treatment and for the treatment of any relapse (Table 4).

Summation of local therapy given both as part of initial

treatment and for the treatment of relapse indicated that the

utilization of significant local treatment was less in the

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European studies when analyzed collectively (74%) as

compared with patients treated in the IRS studies, of whom

91% at least received radiation therapy. Among the Euro-

pean groups, 41% of the surviving SIOP patients had beencured without radiation therapy or radical surgery, com-

pared with 7% for ICG patients and 20% for CWS patients.

Prognostic Factors

Analysis of 10-year OS rates by prognostic variables are

listed in Table 5 for the whole population. Survival differed

by age and histologic subtype. Age less than 3 years was

associated with a less favorable outcome (P .004).Histology was also correlated with survival, with an unfa-

vorable outcome for patients with alveolar histology and

embryonal sarcoma compared with patients with embryonal

RMS (P .001). Sex, tumor size, T stage, clinical group,

and era of therapy did not correlate with outcome. Age and

histology seem to be correlated factors: the mean age at

diagnosis of children with embryonal RMS was 6.7 years,

which is significantly older than patients with alveolar

histology (mean age, 5.5 years). However, histology main-

tained its prognostic value after adjustment for age (P

.001), and age remained significant even after adjustment

for histology (P .007). Relative risks of death were 1.57,

1.6, and 8.8 for patients younger than 3 years with favorable

histology, patients older than 3 years with unfavorable

Table 2. Details of Radiation Treatment as Primary Treatment

Total IRSG CWS ICG SIOP

No. of patients 306 186 40 37 43Patients irradiated

No. 245 173 28 28 16

% 80 93 70 76 37 Total dose, Gy

Median 45 45 32 46 45

Range 6-64 6-60 25-72 40-70 39-64Missing data 29 27 2 0 0

No. of patients irradiatedyounger than 3 years

33 27 2 2 2

Table 3. Outcome

Total IRSG CWS ICG SIOP

No. of patients 306 186 40 37 43Patients achieving complete remission

No. 294 13 40 37 42% 96 94 100 100 98

Patients experiencing relapse

No. 51 13 10 13 15% 17 7 25 35 36Local, n 44 9 8 12 15Local metastatic, n 3 0 2 1 0

Metastatic,* n 4 4* 0 0 0Local relapse rates in relation to use of radiation therapy

No. of patients not irradiated 61 13 12 9 27 Patients experiencing local relapse

No. 27 3 4 7 13% 44

No. of patients irradiated 245 173 28 28 16Patients experiencing local relapse

No. 20 6 6 6 2% 8

Status of patients at last follow-up

Alive 273 170 35 31 37In first CR 238 160 28 24 26In CR after relapse 26 3 7 6 10With disease 9 7 0 1 1

Dead 33 16 5 6 6Without first CR 7 6 0 0 1After relapse 21 8 3 6 4From therapy 4 1 2 0 1Unknown cause 1 1 0 0 0

Abbreviation: CR, complete remission.*Patterns of metastatic relapse: one bone marrow; one bone marrow brain; one bone marrow bone; one bone marrow bone eye (all embryonal RMS).



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DISCUSSION

Children with orbital RMS have an excellent prognosis

for cure. The results of this analysis of 306 patients without parameningeal extension, regional lymph node involve-

ment, or distant metastatic disease show a 10-year OS rate

of 87%, regardless of the initial approach to therapy.

Nevertheless, the risk of late sequelae of treatment is

significant, particularly in relation to the consequences of

local therapy. The most comprehensive published review of

the late effects induced by radiotherapy derives from the

report of experience from the IRSG I study.4 This study of

50 children surviving more than 6 years after treatment in

the IRS I study and incorporating radiation to the orbit at

doses between 50 and 60 Gy showed late effects that

included reduced vision (80%), cataract (92%), orbital

hypoplasia (52%), and facial asymmetry (41%). Thirteenpatients (27%) had required surgery for cataract extraction,

correction of ptosis, or dilatation of the lachrymal ducts, and

four patients (8%) had had late enucleation for the compli-

cations of therapy. Sixty-one percent had evidence of

growth impairment. These data, however, derive from a

treatment strategy initiated 20 years ago, and subsequent

improvement in radiation techniques may have reduced the

incidence or lessened the severity of such sequelae. Never-

theless, total radiation doses of more than 45 Gy remain

in current practice, and preliminary data from patients

treated in IRS III from 1984 through 1991 suggest that

changes in equipment, planning techniques, or fraction-ation schedules are unlikely to have significantly dimin-

ished the problems encountered.9 Data from patients

treated at higher doses (55 to 60 Gy) suggest higher rates

of visual loss.10 The results of the analysis of the

European patients in this study and the data recently

published by the IRS group confirm that similar problems

arise in patients treated in more recent eras (Table 6). The

debate should focus on whether it is possible to cure

patients with orbital RMS without local treatment and, if

Fig 4. OS according to initial radiotherapy: radiotherapy, 86% (range,82% to 93%); no radiotherapy, 86% (range, 77% to 95%).

Table 5. Overall Survival Rate by Prognostic Variables

Total No. DeathsOS at 10

Years (%)Relative

Risk Significance

Age

3 years 50 12 68 3.3 3 years 256 21 90 1 P .004

HistologyEmbryonal sarcoma or

alveolar RMS39 11 68 3.6

Embryonal RMS 267 22 90 1 P .001

SexMale 157 17 88Female 149 16 86 NS

Tumor size

5 cm 219 22 88 5 cm 21 2 90 NSUnknown 66 9

Clinical groupComplete removal 9 3 78Microscopic residue 38 2 97 Macroscopic residue or

biopsy259 23 89 NS

RadiotherapyYes 245 25 87No 61 8 86 NS

Collaborative groupIRS 186 16 88CWS 40 5 87 ICG 37 6 86SIOP 43 6 85 NS

Era of therapy1978-1983 85 11 88*1984-1988 125 14 91* 1989 96 8 91* NS

Abbreviation: NS, not significant.*5-year OS.

Table 6. Late Sequelae of Treatment

Type of Sequelae

European Patients(pooled data) IRSG Pat ien ts*

No. of SurvivorsAffected %

% Survivors Affected(n 94)

Globe removed 9/83 11 14Cataract 36/71 51 82Reduced vision in affected eye 37/68 54 70Dry eye 20/72 28 23Painful eye 10/72 14 14Keratitis 10/72 14 18Corneal ulcer 4/72 6 4

Retinal damage 8/72 11 3Ptosis 26/72 36 28Orbital hypoplasia 27/72 29 59Maxillary hypoplasia 7/72 10 11

*IRSG data based on data from patients treated in the IRS III study. 9



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so, at what cost in terms of any diminution of survival or

in the expression of alternative late effects of treatment

relating to chemotherapy.

Data from this study do not permit any clear conclusions

to be made about the efficacy, or otherwise, of reduced-dose

radiotherapy. To date, the efficacy of doses less than 40 Gy

is unproved and any significant reduction in the adverse

effects on facial growth and visual function would not be

expected until the total dose administered was substantially

below this level. Indeed, cataract formation is reported at

radiation doses below 10 Gy.11

The concept of the total burden of therapy is important in

considering the cost of survival, particularly in patients who

survive after relapse and who have therefore been exposed to

additional treatment. It is often the case that the disadvantages

of radiotherapy are more obvious clinically than the sequelae

resulting from chemotherapy; longer follow-up and careful and

systematic investigation are required to determine the inci-

dence and importance of some of the other possible conse-

quences of treatment, eg, infertility after exposure to alkylating

agents and cardiotoxicity after anthracycline exposure, as well

as the risk of second malignancy induced by both chemother-

apy and radiotherapy.

Detailed data relating to the quality control of radiation

therapy were not available for all patients in this study.

Overall, the local failure rate for patients treated with

radiotherapy was small (8%; Table 3), confirming the

efficacy of such treatment, and although the incidence of

relapse after radiotherapy was higher in the European

studies, the results do not permit clear conclusions to be

made to explain this in terms of the dose given. Other

variables that may influence the efficacy of local control

achieved with radiotherapy include the criteria for selection

of patients for such treatment (for example, in relation to

chemotherapy response, histology, and age) and the quality

of treatment given.

Nevertheless, it is clear that important late effects are

encountered by a significant number of survivors, and the

experience of the strategy promoted by the SIOP group

illustrated in this study and reported previously by

Rousseau et al3 suggests that up to 40% of patients with

localized RMS of the orbit can be treated successfully

without the use of radiotherapy and without disadvantage

to the survival of the whole group. The challenge for the

future must be to identify the characteristics shown by

patients who can be safely treated in this manner without

a significant risk of relapse and to ensure that radiation

therapy is delivered to the remaining patients in a manner

that is both effective and offers the least chance of

unacceptable late sequelae.

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Rhabdomyosarcoma Study. J Clin Oncol 13:610-630, 1995

3. Rousseau P, Flamant F, Quintana E, et al: Primary chemotherapy

in rhabdomyosarcoma and other malignant mesenchymal tumours of

the orbit: Results of the International Society of Paediatric Oncology

MMT 84 Study. J Clin Oncol 12:516-521, 1994

4. Heyn R, Ragab A, Raney RB, et al: Late effects of therapy in

orbital rhabdomyosarcoma in children: A report from the Intergroup

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