Medical and Pediatric Oncology 33:362–371 (1999)

Late Complications of Therapy in 213 Children With Localized, Nonorbital

Soft-Tissue Sarcoma of the Head and Neck: A Descriptive Report From the
Intergroup Rhabdomyosarcoma Studies (IRS)-II and - III
R. Beverly Raney, MD,1* Lina Asmar, PhD,2 Rena Vassilopoulou-Sellin, MD,3
Mary Jean Klein, RN,3 Sarah S. Donaldson, MD,4 Jennifer Green,2
Ruth Heyn, MD,5 Moody Wharam, MD,6 Arvin S. Glicksman, MD,7
Edmund A. Gehan, PhD,2 James Anderson, PhD,8 and Harold M. Maurer, MD,9
for the IRS Group of the Children’s Cancer Group and the Pediatric Oncology Group

Background. This review of children and
adolescents with nonorbital soft-tissue sarcoma
of the head and neck was undertaken to de-
scribe late sequelae of treatment, as manifested
primarily by problems with statural growth, fa-
cial and nuchal symmetry, dentition, vision and
hearing, and school performance. Procedure.
Four hundred sixty-nine patients entered the
IRS-II and -III protocols with localized, nonor-
bital soft-tissue sarcomas of the head and neck
from 1978 through 1987. Their overall survival
rate was 53% (250/469) at 5 years. Two hun-
dred thirteen patients were surviving relapse-
free 5 or more years after diagnosis, for whom
there were serial height measurements at 2 or
more years after initiation of therapy. Their me-
dian age at diagnosis was 5 years; the median
length of follow-up was 7 years. All received
multiple-agent chemotherapy, and all but 3 re-
ceived irradiation to the primary tumor volume.
Sixty-eight percent of the tumors arose in cra-
nial parameningeal sites, 22% in nonparamen-
ingeal sites, and 10% in the neck. We reviewed
flow sheets submitted to the IRS Group Statisti-
cal Office to ascertain which late sequelae
were recorded. Results. One hundred sixty-four
patients (77%) had one or more problems re-
corded. One hundred ninety of the two hun-
dred thirteen patients (89%) were under 15
Key words: late sequelae; head/neck sarcoma; childhood
years of age at study entry, and at follow-up 92
(48%) had failed to maintain their initial height
velocity, which had decreased by more than 25
percentile points from the original value.
Thirty-six of the one hundred ninety patients
(19%) were receiving growth hormone injec-
tions. Hypoplasia or asymmetry of tissues in the
primary tumor site was reported in 74 patients,
and 13 underwent reconstructive surgery. Poor
dentition or malformed teeth were noted in 61
patients. Impaired vision developed in 37 pa-
tients, owing primarily to cataracts, corneal
changes, and optic atrophy. Thirty-six patients
had decreased hearing acuity, and 9 were fitted
with hearing aids; 5 of these 9 had received
cisplatin. Thirty-five patients were noted to
have problems learning in school. Four patients
developed a second malignancy (two sarco-
mas, one carcinoma, one leukemia). Conclu-
sions. Late sequelae affected the majority of
these patients treated for soft-tissue sarcoma of
the head and neck on IRS-II and -III. The po-
tential impact of certain sequelae could be re-
duced by specific measures, such as surgical
reconstruction and hormonal therapy. Late se-
quelae must be taken into account in designing
future curative treatments. Med. Pediatr. Oncol.
33:362–371, 1999. © 1999 Wiley-Liss, Inc.

1
Department of Clinical Pediatrics, The University of Texas M.D. Presented in part at the 26th Meeting of the International Society of
Anderson Cancer Center, Houston, Texas Paediatric Oncology (SIOP) in Paris, France, on September 23, 1994;
2
The Pediatric Intergroup Statistical Office, Houston, Texas, and at the 87th Annual Meeting of the American Association for Cancer
Washington, DC Research in Washington, DC, on April 21, 1996; and at the 30th
3
Section of Endocrinology, The University of Texas M.D. Anderson Meeting of the SIOP in Yokohama, Japan, on October 7, 1998.
Cancer Center, Houston, Texas Grant sponsor: National Cancer Institute; Grant numbers: CA-24507,
4
Department of Radiation Oncology, Stanford University Medical CA-30138, CA-29511.
Center, Stanford, California The IRS Group of the Children’s Cancer Group and the Pediatric
5
Department of Pediatrics, University of Michigan, Ann Arbor, Michi- Oncology Group includes Richard J. Andrassy, MD, Charles Bagwell,
gan MD, W. Archie Bleyer, MD, John Breneman, MD, William Crist, MD,
6
Christopher Fryer, MD, Michael Link, MD, Thom Lobe, MD, Sharon
Division of Radiation Oncology, Johns Hopkins Oncology Center, Murphy, MD, William Newton, MD, Jorge Ortega, MD, Frederick
Baltimore, Maryland Ruymann, MD, Timothy Triche, MD, PhD, Teresa Vietti, MD, Bruce
7
Quality Assurance Review Center, Department of Radiation Oncol- Webber, MD, and Eugene Wiener, MD.
ogy, Royer Williams Cancer Center, Providence, Rhode Island *Correspondence to: Dr. R.B. Raney, Department of Pediatrics, Box
8
The Pediatric Intergroup Statistical Office, Omaha, Nebraska 87, The University of Texas M.D. Anderson Cancer Center, 1515
9
Office of the Dean, University of Nebraska Medical School, Omaha, Holcombe Blvd., Houston, TX 77030.
Nebraska Received 28 August 1998; Accepted 22 April 1999
© 1999 Wiley-Liss, Inc.
 Late Sequelae of Head/Neck Sarcoma in Childhood 363

INTRODUCTION TABLE I. Radiation Therapy Doses Used in IRS-II and IRS-III

The most common types of malignant soft-tissue tu- Age Tumor Total
Clinical group (years) size (cm) dose (Gy)
mors in childhood are rhabdomyosarcoma (RMS) and
IRS-II
undifferentiated sarcoma (US) [1]. Approximately 35% II 0–20 Any 40–45
of these tumors arise in the head and neck, that is, above III 0–5 <5 40–45
the clavicles anteriorly and above the C7 vertebral body III 6–20 <5 45–50
posteriorly. There are three broad anatomical groups of III 0–5 >5 45–50
these lesions: orbital tumors, nonorbital cranial para- III 6–20 >5 50–55
IRS-III
meningeal tumors, and nonparameningeal tumors of the II 0–20 Any 41.4
head and neck [2–5]. Tumors in the head and neck are III 0–5 <5 41.4
difficult to remove in toto with wide, uninvolved mar- III 6–20 <5 45
gins, and radiation therapy is usually needed to secure III 0–5 >5 45
local control. Multiple-agent chemotherapy programs for III 6–20 >5 50.4
these patients have involved administration of two to six
drugs over 1–2 years, to treat the local tumor and occult courses of cisplatin at 90 mg/m2 per course in the induc-
metastases. tion period, and one-half of them also received etoposide
The Intergroup Rhabdomyosarcoma Study Group [8]. The other 20% received VAC without the additional
(IRSG) was formed in 1972 to study the biology and three drugs. The treatment period was 2 years for patients
treatment of pediatric and adolescent RMS and US. The with Group III disease and 1 year for patients with mi-
outcome for patients with RMS and US has improved croscopic (Group II) or no residual tumor (Group I).
over a series of IRSG protocols, so that 60–80% of pa- Intrathecal chemotherapy. In both IRS-II and IRS-
tients are now cured with current management [6–8]. III, patients with signs of meningeal impingement (e.g.,
This paper presents results of a descriptive review of cranial nerve palsy, bony erosion at the skull base, and/or
5-year, relapse-free survivors of localized nonorbital intracranial extension) were also given periodic intrathe-
RMS and US of the head and neck in childhood who cal injections of methotrexate, hydrocortisone, and cyto-
were initially entered on the IRS-II (1978–1984) and sine arabinoside by lumbar puncture, as outlined in the
IRS-III (1984–1987) protocols [7,8]. Late effects in 56 protocols. The doses were adjusted by body surface area,
patients with primary orbital sarcoma treated on IRS-I with a maximum dose of 15 mg methotrexate per injec-
(1972–1978) were reported previously [9]. tion [7,8].
Radiation therapy (XRT). Protocol-specified therapy
MATERIALS AND METHODS included megavoltage XRT for patients with known re-
sidual locoregional disease (Groups II and III). In both
Patients with localized, nonorbital RMS or US of the studies, doses were based on age of the patient and great-
head and neck who were entered on the IRS-II and -III est diameter of the primary tumor at diagnosis, as shown
protocols from 1978 through 1987 were previously un- in Table I. The daily dose was 1.8 Gray (Gy), 5 days per
treated and under 21 years of age at diagnosis. Patients week, with allowance for a reduced fraction size to 1.5
with extraosseous Ewing sarcoma (EOE) [10] were also Gy for large treatment volumes. The protocols specified
eligible for study entry. The diagnosis of RMS, US, or XRT portals to include a 5-cm margin around the tumor
EOE was confirmed by members of the IRSG Pathology as imaged at the time of diagnosis. Patients whose tumors
Subcommittee. showed one or more signs of meningeal impingement
also received whole-brain irradiation to a total dose of 30
Treatment
Gy if 6 years of age or older or 24 Gy if younger than age
Systemic chemotherapy. The evaluation of extent of 6 years at diagnosis. Whole spinal XRT was given to
disease at diagnosis and the details of subsequent treat- similar patients early in IRS-II using the same dosage and
ment have been published [7,8]. In brief, all patients with age provisions as whole-brain XRT, but this practice was
head and neck sarcoma received chemotherapy with vin- discontinued in December, 1980. Informed consent was
cristine and actinomycin D (VA). Ninety percent (192/ obtained for each patient registered on IRS-II and -III.
213) of these patients also received intravenous cyclo- The site-specific, off-axis doses of radiation to spe-
phosphamide (C), and approximately one-half also re- cific structures, including the pituitary and thyroid gland
ceived doxorubicin (DOX). Actinomycin D and DOX and the eye, were calculated by two of the authors (M.W.
were withheld during radiation treatment. In IRS-III, ap- and A.S.G.) following review of simulator and portal
proximately 80% of patients with localized, gross re- films and dosimetry records, for the patients who were
sidual tumor (Group III) were randomized to receive four identified with complications potentially related to XRT.
364 Raney et al.
Such calculations were not undertaken for patients who
did not have late sequelae recorded as affecting these
structures.
Flow-Sheet Review
A total of 469 eligible patients with localized, nonor-
bital sarcoma of the head and neck were entered on IRS-
II and -III. Two hundred fifty patients were alive and
relapse-free at the time of this review. Thirty-seven pa-
tients were excluded because statural growth data were
missing (N ⳱ 27), follow-up was less than 5 years (N ⳱
9), or XRT information was inadequate (N ⳱ 1). Thus,
data on 213 patients who were relapse-free and alive for
5 years or more, with serial height measurements re-
corded for a minimum of 2 years, were available. Reports
from surgical procedures, pathology information, and
XRT reports were reviewed, along with dated flow
sheets, which displayed chemotherapy doses as well as
the results of physical, laboratory, and radiographic
examinations. Data regarding statural growth and devel-
opment, endocrinologic status, facial and/or nuchal
asymmetry, dental status, vision and hearing, and school
performance were also reviewed. The reports were sub-
mitted by data managers/clinical research assistants and
physicians at approximately 100 institutions who were
members of the Children’s Cancer Group and the Pedi-
atric Oncology Group. No nursing notes were available,
and no further information was sought from the partici-
pating institutions, schools, patients, or parents. It should
be emphasized that there was no formal system in place
at the time when the IRS-II and -III protocols were in use
to capture information about complications of the disease
and therapy. Thus the abnormalities reported herein are
likely to be underestimated.
Enumeration of Late Sequelae
Patients were categorized into eight groups: no late
effects recorded or one to seven late effects noted in the
areas of interest: growth, facial/nuchal asymmetry, den-
tition, vision, orbital problems, hearing, and schooling.
For example, patients given thyroid hormone because of
documented hypothyroidism were scored as having a late
effect, whereas those given thyroid hormone as an ad-
junct to treatment with growth hormone (but without
known hypothyroidism) were scored only once, for
growth hormone replacement. Patients who had a pri-
mary tumor of the face or pharynx with cervical lymph
node metastasis and who received XRT to both the pri-
mary and regional nodes were considered to have one
late effect if hypoplasia/asymmetry was noted in one or
both sites. Dental problems were considered as one late
effect, regardless of how many teeth were affected. Pa-
tients with visual problems affecting one or more ocular
structures (e.g., conjunctiva, cornea, lens, and retina)
were scored as having one late effect, regardless of the
number of distinct ocular sites affected. Patients with
ptosis, enophthalmos, or orbital hypoplasia were scored
separately. Patients with diminished hearing were con-
sidered to have one late effect, whether it was due to
tumor (e.g., middle-ear tumor with disruption of the con-
ductive apparatus) or treatment. Patients having one or
more difficulties with schooling (e.g., memory problems
in addition to reading difficulty) were scored as having
one late effect, a problem with learning.
Evaluation of Statural Growth
The initial height measurement at time of registration
in the study was used as the first measurement. The most
recent measurement available at follow-up was plotted
on a standard growth chart and compared to recent prior
values for accuracy. Patients were ranked into six height
categories according to their initial height, and deviations
from the initial category were recorded, using the most
recent height measurement. The categories were defined
as: >95th percentile of the expected value for age and
gender, 75–95th percentile, 50–74th percentile, 25–49th
percentile, 5–24th percentile, and <5th percentile. Any
patient whose height category decreased from the initial
one by two or more of these percentile categories was
considered to have subnormal growth velocity.
RESULTS
The 213 patients were 1 month to 20 years of age at
the time of study entry (median 5 years) and were 5–32
years old at follow-up (median 12 years). One hundred
and forty-four patients (68%) had cranial parameningeal
tumors, 48 patients (22%) had cranial nonparameningeal
tumors, and 21 patients (10%) had primary tumors in the
neck. The primary sites and the number of patients in
each clinical group are shown in Table II. One hundred
ninety-two of the two hundred thirteen patients (90%)
received intravenous cyclophosphamide in addition to
vincristine and actinomycin D, and 99% received radia-
tion therapy.
There were no late effects recorded on the flow sheets
of 49 patients. The remaining 164 patients (77%) had one
or more sequelae of the disease or treatment recorded.
Sixty-five had one sequela, 38 had two, 32 had three, 15
had four, 9 had five, 4 had six, and 1 had seven late
effects noted. The location of the late sequelae, as ex-
pected, was related to the primary tumor site. Table III
shows the major categories of these problems. The most
frequent difficulties involved poor statural growth, facial/
nuchal asymmetry, dental abnormalities, impaired vision,
decreased hearing, and impaired learning in school.
 Late Sequelae of Head/Neck Sarcoma in Childhood 365
TABLE II. Distribution of Primary Tumor Sites and TABLE III. Late Effects Reported in Patients With Nonorbital
Clinical Group Head and Neck Sarcoma
Group Group Group No. reported/ Percentage
Primary site I II III Totals Category No. at risk reported
Parameningeal (N ⳱ 144) Poor statural growth 92/190a 48
Nasopharynx/nasal cavity 1 4 52 57 Facial/nuchal asymmetry 74/213 35
Middle ear 1 36 37 Poor dentition 61/213 29
Pterygoid/infratemporal fossa 2 19 21 Decreased vision 37/213 17
Paranasal sinus 2 27 29 Decreased hearing 36/213 17
Nonparameningeal (N ⳱ 48) Poor school performance 35/213 16
Oropharynx 1 6 6 13 a
One hundred ninety patients under 15 years old at diagnosis were
Parotid 1 8 9
considered capable of further growth.
Scalp 8 1 9
Cheek 3 6 9
External ear 3 1 4 mone in addition to growth hormone (Table V). Thirteen
Larynx 2 2
Masseter 2 2
of these seventeen patients (76%) had received direct
Neck (N ⳱ 21) 1 5 15 21 irradiation of the thyroid gland at a median dose of 45 Gy
Totals 3 37 173 213 (range 28.5–50.4 Gy). Their median age at diagnosis was
9.1 years (range 1.3–14.8 years). Another group of 24
patients received no thyroid hormone replacement
Growth and Development therapy but had received XRT to a portion of the neck in
Statural growth. One hundred ninety of the two hun- which thyroid tissue would be present. Twenty-three of
dred thirteen patients (117 boys, 73 girls) were under 15 these patients received a median dose of 39.6 Gy (range
years of age when registered in the study and were con- 11.7–55.5 Gy); one had no data recorded. The median
sidered capable of further statural growth. At last follow- age at diagnosis of these 23 patients was 7.4 years (range
up, varying from 2–7 years or more, 92 patients (48%) 1.3–19.2 years), comparable to the 13 who were taking
had failed to maintain their growth velocity. Forty-eight thyroid hormone after neck irradiation.
patients’ latest height measurements were lower by two Pubertal development. Thirty-one patients who were
height categories, 37 by three, and 7 by four or five under 15 years of age at diagnosis had sufficient recorded
height categories compared to their initial measurement. information for assessment. Twenty-six were progressing
There was no difference in likelihood of diminished or had progressed normally through puberty. Three fe-
growth by age at diagnosis during the first decade of life: males had abnormal development. One had early breast
of those under 5 years old when diagnosed, 51% had growth at age 6.7 years. Another girl had delayed pu-
subnormal growth (i.e., a decrement of two or more berty, with menarche at age 19 years; she had received
height categories) compared to 54% of those aged 5–9 58.5 Gy to the paranasal sinuses. Another female had
years and 21% of those aged 10–14 years at diagnosis. signs of early puberty at age 14 years but had not men-
Thirty-six of these one hundred ninety patients (19%), struated; she had received 50.6 Gy to the infratemporal
including 26 boys and 10 girls, received growth hormone fossa. Both of these females had also received intrave-
according to individual criteria, after completing chemo- nous cyclophosphamide for 2 years. Three males were
therapy and XRT for the sarcoma (Table IV). There was also affected adversely. One was receiving injections of
no indication of a dose–response relationship in these 36 testosterone, and one was azoospermic at age 18 years.
patients, nor of any influence of a particular regimen of The last, 18 years of age at diagnosis, had atrophic tests
chemotherapy. The data available indicated that statural at age 23 years, and was considered sterile. All three
growth improved after administration of growth hor- young men had been treated with cyclophosphamide.
mone, and there were no reported complications. All but Marriage and offspring. Two males and one female
one of the patients given growth hormone had a cranial were married. Three other females had given birth to a
parameningeal primary tumor. Their median age at diag- daughter, and another was 6 months pregnant at the time
nosis was 4.1 years (range 0.9–10 years) and they had of last follow-up. There were no reported congenital ab-
received a median dose of 45 Gy to the pituitary gland normalities or miscarriages.
(range 30–57.6 Gy). One of the 36 patients also received
Facial/Nuchal Symmetry and Cosmesis
cortisone acetate because of partial adrenocorticotropic
hormone (ACTH) deficiency. Among 76 patients for whom there was information
Thyroid hormone replacement. Sixty-eight patients about their facial and/or nuchal symmetry, two patients
had results of thyroid function tests; sixty-two of them were noted to have no hypoplasia or asymmetry, whereas
were normal. Eight patients were taking thyroid hormone 74 had asymmetry or hypoplasia at the site of the primary
alone, and nine other patients were taking thyroid hor- tumor. Thirteen of these seventy-four patients (18%) had
366 Raney et al.
TABLE IV. Pituitary Irradiation in 36 Patients Given Human Growth Hormone
Age (years) Estimated XRT dose Change in
at diagnosis Gender Site of tumor (Gy) to pituitary gland height group
0.9 M Nose 45 −2
1.1 F Middle ear 42 −2
1.3 M Infratemporal 40–45 −3
1.9 M Middle ear 43.6 −1
2.0 M Temporal 36.9 −1
2.1 F Nose 45 0
2.1 M Middle ear 45.0 −1
3.0 M Middle ear 45.0 −2
3.0 M Middle ear 39.8 0
3.0 M Nasopharynx 41.4 −2
3.1 M Middle ear 55.4 −3
3.1 M Nasopharynx 46.0 −4
3.3 F Middle ear 44.0 −1
3.7 M Nasopharynx 45.0 −3
3.8 F Sinus 49.5 −2
3.9 F Middle ear 40.8 −3
4.0 M Nose 44.4 −1
4.1 F Nasopharynx 44.9 Whole brain −2
4.1 M Nasopharynx 52.3 −1
4.6 F Nasopharynx 57.6 0
5.0 M Infratemporal 44.4 −2
5.1 M Nasopharynx 30–35 Whole brain −3
5.1 M Nasopharynx 41 −2
5.1 M Middle ear 55.8 −1
5.4 M Ethmoid 49.56 −2
5.6 F Nasopharynx 56.0 −3
5.6 F Nasopharynx 50.4 −2
6.0 M Temporal 54.0 −1
6.0 M Nasopharynx 55.5 0
6.1 M Middle ear 50.4 −4
6.1 M Nasopharynx 50.4 −1
9.1 F Pterygoid 49.2 −1
9.3 M Ethmoid 56.6 −3
9.3 M Parotid 50.4 −2
9.9 M Nasopharynx 50.4 0
10.0 M Middle ear 38.1 −3

undergone one or more plastic surgical reconstructive
procedures.
Dentition
The flow sheets of 61 patients contained information
about dental abnormalities. The patients’ median age at
diagnosis was 5.3 years (range 0.2–19.2 years); the me-
dian XRT dose to the primary tumor was 46.0 Gy (range
37.7–68 Gy). No assessment of severity was made in the
vast majority of patients (58/62; 94%). The remaining
four patients were said to have severe dental problems.
The abnormalities were multiple caries (N ⳱ 27 pa-
tients), followed by malformed teeth (N ⳱ 20), “poor
dentition” (N ⳱ 11), and missing teeth (N ⳱ 3). Eleven
of these sixty-one patients (18%) had undergone a dental
surgical procedure (other than restorations or application
of braces) such as dental extraction.
Eye Problems and Visual Impairment
Forty-five patients with eye problems were identified.
Seven had chronic conjunctivitis, and another had a dry
eye. Thirty-seven other patients had visual impairment.
Among them, 19 had a unilateral cataract, including 1
with retinopathy and dry eye and another with retinal
hemorrhage. Two others had bilateral cataracts. Six of
these twenty-one patients underwent cataract extraction.
Three other patients underwent enucleation because of
corneal perforation (N ⳱ 2) or severe keratitis (N ⳱ 1).
Four patients had unilateral corneal opacity, including
one with dry eye. One each had retinopathy, retinal hem-
orrhage, bilateral blindness, or chronic conjunctivitis in-
terfering with vision. Four additional patients were blind
with unilateral optic atrophy attributed to the tumor, and
another had visual impairment not otherwise specified.
Thirty-five of these thirty-seven patients with visual im-
pairment had juxtaorbital tumors affecting primarily
parameningeal sites, including the nasopharynx, parana-
sal sinuses, or infratemporal fossa; two patients had tu-
mors of the cheek. Table VI shows the age, dose of
radiation therapy to the primary tumor and to the eye, and
type of problem in the 32 patients who developed visual
 Late Sequelae of Head/Neck Sarcoma in Childhood 367
TABLE V. Thyroid/Neck Irradiation in 17 Patients Given Thyroxine*
Age (years) Estimated XRT Estimated XRT T4 HGH
at diagnosis Gender Site of primary tumor dose (Gy) to thyroid dose (Gy) to primary Rx. Rx.
1.3 M Infratemporal 40–45 44.0 + +
1.9 M Middle ear 0 43.6 + +
2.8 F Nasopharynx, neck LN 45.6 45.6 + ND
3.0 M Temporal 46.0 46.0 + ND
3.8 F Sinus 0 49.8 + +
4.3 F Nasopharynx 45.5, Upper 1⁄2 45.5 + ND
4.5 M Oropharynx 28.8, Posterior 28.8 + 0
4.6 F Nasopharynx 30.6 57.6 + +
5.6 F Nasopharynx 0 50.4 + +
9.1 F Pterygoid 28.5 49.2 + +
9.3 M Parotid 50.4 50.4 + +
9.3 M Ethmoid 0 56.6 + +
9.9 M Nasopharynx 50.4, Upper 1⁄2 54.0 + +
11.4 M Oropharynx, neck LN 45.0 45.0 + ND
11.9 F Neck 40.0 40.0 + 0
12.3 M Neck 38.18 38.0 + 0
14.8 M Larynx 46.8 46.8 + ND
*T4, thyroxine; HGH, human growth hormone; Rx., therapy; LN, lymph nodes; +, therapy given; 0, no therapy given; ND, no data. Patients
treated with HGH had earlier received pituitary irradiation and also appear in Table IV. Four patients receiving no thyroid XRT were given T4
along with HGH.

impairment after treatment of the sarcoma (excluding the
5 with optic atrophy or unspecified impairment). Extra-
ocular problems included ptosis (N ⳱ 15), hypoplastic
orbit (N ⳱ 8), enophthalmos (N ⳱ 4), and strabismus (N
⳱ 3). Six children were reported with more than one of
these extraocular abnormalities.
Ears and Auditory Problems
Thirty-six patients had impaired hearing. Their pri-
mary tumors arose in the middle ear (N ⳱ 18), naso-
pharynx-nasal cavity (N ⳱ 8), the pterygoid region/
infratemporal fossa (N ⳱ 5), paranasal sinus (N ⳱ 2),
and ear canal, parotid, or the neck (N ⳱ 1 each). The
patients’ median age at diagnosis was 4.7 years (range
1.3–19.1 years). They received XRT to the primary site
to a median total dose of 45.8 Gy (range 39.6–57.6 Gy).
Nineteen patients received chemotherapy without cis-
platin; the other 17 patients also received cisplatin. Hear-
ing aids were being worn by 9 young patients (median
age at diagnosis 3.6 years; range 1.3–5.8 years). Five of
these nine had received cisplatin and wore bilateral hear-
ing aids. Five of the nine also had primary sarcoma of the
middle ear; 2 received cisplatin and 3 did not.
School Performance, Behavior Problems, and Central
Nervous System Dysfunction
Educational status. Seventy-one patients’ flow sheets
contained information about schooling. Thirty-four pa-
tients were in age-appropriate classrooms, including sev-
eral who were in college, and one additional patient was
being schooled at home. One teenager had dropped out of
school. The remaining 35 patients were reported to have
various learning disabilities. Twenty-two of these pa-
tients had received whole-brain XRT at a median dose of
30 Gy (range 6–33 Gy); 16 of them also received triple
intrathecal (IT) medications (median 11 or 12 injections;
range 4–15 injections). Seven additional patients re-
ceived a median of 11 triple IT medication courses (range
6–13) but no whole-brain XRT, and the remaining 6
patients received neither IT medications nor brain XRT.
The most frequently identified difficulties involved speech
in 9 patients, mathematics in 8 patients, reading in 5
patients, and memory in 5 patients; the remaining pa-
tients had nonspecified learning disabilities. There was
no apparent relationship between a specific disability and
delivery of brain XRT. The relative contributions of the
IT agents and/or brain XRT to the learning problems
could not be distinguished.
Behavior problems. Difficulties with behavior were
reported in 16 patients, and a lack of behavior problems
was specifically noted in 5 others. The reported problems
included hyperactivity; immaturity; depression; and un-
cooperative, manipulative, or suicidal behavior. Only one
of the patients cited with behavioral difficulties had re-
ceived brain irradiation and IT medications.
Central nervous system dysfunction. Eight patients
were reported with impairment. A 7-year-old with a na-
sopharyngeal primary tumor became blind from bilateral
optic atrophy after 51.7 Gy to the nasopharynx and 31.5
Gy to the whole brain along with two courses of triple IT
medications; the eyes had not been shielded during the
radiation. A three-year-old had seizures and severe men-
tal retardation attributed to cerebral vascular abnormali-
ties after 60 Gy to the left middle ear and 27 Gy to the
whole brain, along with 11 courses of triple IT drugs. A
2-year-old had a seizure and poor balance 7 years after
368 Raney et al.
TABLE VI. Age, Radiation Dose, and Impaired Vision in 32 Patients*
XRT dose
Age (years) to primary
at diagnosis Gender Site of tumor (Gy) Estimated XRT dose to eye (Gy) Complication(s)
0.7 F Paranasal sinus 42.1 R eye, 39.9; L eye, medial 1⁄2, R cataract
37.8
1.0 F Paranasal sinus ≅36 R lens, 1.9; anterior 1 cm, 46.8; R cataract, retinopathy, dry eye
remainder, 65.8
1.0 M Ethmoid 40.5 R lens, 5.4 R cataract, enophthalmos
2.3 M Cheek 45.0 L eye, 45.0 L perforated cornea → enucleation
2.7 F Paranasal sinus 45.0 L eye, 40.0 L chronic conjunctivitis
2.8 F Nasopharynx 45.6 R eye, 45.6; L eye, 45.6 Bilateral cataracts
3.3 M Ethmoid 45.0 L eye, 9.0; R eye, 45.0 R cataract
3.5 F Cheek 45.3 R eye, 45.3 R cataract
3.7 F Paranasal sinus 50.6 L eye, anterior, 25.3; remaining, L cataract
50.6
3.8 F Paranasal sinus 49.8 R eye, anterior, 20.0; posterior, R cataract
50.0
3.8 M Infratemporal 46.8 L eye, 46.8 L cataract, retinal hemorrhage
3.8 M Maxillary sinus 43.4 L lens, 44 L cataract
4.8 M Nasopharynx 51.2 L eye, 14.8; R eye, 14.8 R corneal opacity
4.8 M Nasopharynx 52.3 L eye, posterior, 48.3; anterior, L cataract
15.3
5.2 F Pterygoid 44.4 R cornea, 0–1.5 R corneal opacity, dry eye
5.3 F Ethmoid 37.7 R eye, anterior, 45.0 R cataract (blind)
5.4 M Ethmoid 49.6 R lens, 36.0 R cataract
5.4 M Pterygoid 39.6 R and L lens, 32.4 Bilateral cataracts
5.7 M Nasopharynx 60.0 R eye, 15.0; L eye, medial 1⁄2, R cataract
15.0
6.2 F Maxillary sinus 45.00 L eye, 45.0; R eye, medial, 22.5 L cataract
6.2 M Nasopharynx 55.5 L eye, 55.5 L keratitis → enucleation
7.4 M Maxillary sinus 50.0 R eye, 45 R cataract
7.7 F Nasopharynx 51.7 L lens, 0; posterior globe, 31.5+ Bilateral blindness
8.7 M Paranasal sinus 54.3 L eye, 54.3 L perforated cornea → enucleation
10.3 M Infratemporal 47.2 R and L cornea, 1.5–2 Corneal opacity
11.7 M Maxillary sinus 55.0 L eye, 55.0; R eye, 7.15 L cataract
12.6 M Maxillary sinus 45.0 R eye, 45.0 R cataract
13.8 M Paranasal sinus 50.4 L eye, 50.4 L retinal hemorrhage
14.0 M Maxillary sinus 60.6 R eye, 53.9 R cataract
15.7 M Nasopharynx 48.2 R and L cornea, 0–1.5 L corneal opacity
18.4 F Nasopharynx 50 L lens, 4.0; remainder, 56.0 L retinopathy
except anterior 1 cm
19.2 M Ethmoid 54.2 L lens, 13.1 L cataract
*R, right; L, left; +, possibly higher. Complications are ipsilateral to the primary tumor unless otherwise stated.

treatment with 23.4 Gy of whole-brain XRT and 12
courses of triple IT medications. A 3-year-old had poor
coordination on the side opposite the site of a paranasal
sinus tumor after 49.8 Gy to the primary tumor and 30
Gy to the brain along with 12 courses of triple IT drugs.
A 5-year-old patient’s neuropsychological tests showed
“borderline intelligence” after 44.4 Gy to the right infra-
temporal fossa and 30 Gy to the brain along with 12
courses of triple IT medications. A 9-year-old developed
“absence” spells after 33 Gy to the brain and triple IT
injections over an 18-month period. The seventh patient
experienced a decrement in IQ from 127 to 100 after
receiving 44.4 Gy to the left middle ear and 30 Gy to the
brain with seven courses of triple IT medications, begun
at age 6.7 years. The eighth patient had mild mental
retardation and had received 46 Gy to the left infratem-
poral fossa and regional cervical lymph nodes at age 3
years but had received neither IT drugs nor whole-brain
XRT.
Second Malignancies
Four patients (4/213; 1.9%) developed a second can-
cer. A 5-year-old received 45 Gy and VAC chemo-
therapy for 2 years for embryonal RMS of the nasophar-
ynx in 1986 and then developed acute myeloid leukemia
5 years after initial diagnosis; he died 2 years later. An-
other 5-year-old received VAC, DOX, and cisplatin and
49.6 Gy for a US of the maxillary sinus. Nearly 6 years
later he developed a small-cell osteosarcoma in the irra-
diated area, from which he died 9 months afterward. A
20-year-old received 35 Gy and VAC with DOX for 2
years for embryonal RMS of the nasal cavity; she had
 Late Sequelae of Head/Neck Sarcoma in Childhood
also received 36 Gy to the craniospinal axis (including 28
Gy to the larynx) beginning in April, 1980. Nine months
after completing therapy she became hoarse and was di-
agnosed with squamous-cell carcinoma of the larynx.
She was then treated with hemilaryngectomy, followed
by 65 Gy to the neck. Seven years later, she developed
lung and then cerebral metastases and died within 9
months. The last patient was a girl initially diagnosed
with bilateral retinoblastoma at 4 months of age. She was
treated with enucleation and XRT. At 12 years of age she
developed alveolar RMS of the right masseter muscle
and received 40 Gy and VA for 1 year. At age 19 years
she was diagnosed with a malignant fibrous histiocytoma
in the right maxillary sinus and skull and received cy-
clophosphamide, DOX, ifosfamide, and etoposide. She
died of progressive histiocytoma at 21 years of age.
Miscellaneous Problems
Two patients were reported with an abnormal echo-
cardiogram after DOX, and two others needed chronic
supplementation with magnesium after cisplatin. No case
of congestive heart failure or renal failure was recorded.
Seven patients were reported with trismus, one of whom
underwent plastic surgery to widen the oral aperture.
Five patients had persistent alopecia in the area of the
primary tumor.
DISCUSSION
This report illustrates many of the complications that
can occur in children successfully treated for head and
neck sarcoma. Because the flow sheets were not designed
to capture late-effects information systematically, the
numbers cited here very likely underestimate the actual
prevalence of late sequelae.
We were interested in evaluating the effect of treat-
ment on statural growth, because diminished height ve-
locity had been noted in 61% of IRS-I patients treated for
orbital rhabdomyosarcoma [9]. Statural growth impair-
ment was also frequent in these patients with nonorbital
sarcomas of the head and neck. Only half of them ap-
peared to grow normally, and 19% of the patients diag-
nosed prior to 15 years of age received growth hormone
injections. In addition, several patients developed hypo-
thyroidism requiring replacement therapy. However, pu-
bertal development and fertility were usually recorded as
unaffected in these patients.
Facial and/or nuchal asymmetry was recorded in ap-
proximately one-third of the patients, and 18% of them
had undergone plastic surgical repair. Dental abnormali-
ties were also described in about one-third of the patients,
and 18% of them underwent dental surgical procedures,
primarily tooth extractions. Problems with vision and
hearing were cited in a minority of the patients. Some of
the impairments could be ameliorated by relatively un-
369
complicated measures, such as cataract extraction or ap-
plication of a hearing aid.
There is limited literature regarding late complications
in children with nonorbital soft-tissue sarcomas of the
head and neck. Cataracts, corneal abnormalities, xeroph-
thalmia, and orbital hypoplasia are well documented as
frequent sequelae in patients treated for orbital sarcoma
or other juxtaorbital tumors with radiation and chemo-
therapy in the era prior to the advent of conformal ra-
diotherapy techniques [9,11–15]. Radiation retinopathy
is relatively unusual in children [16]. Similar problems
can likewise occur after treatment of tumors arising in
adjacent structures (e.g., nasopharynx, paranasal sinuses)
if attention is not given to protecting the sensitive struc-
tures of the eye. Hearing problems resulting from radio-
therapy are unusual; problems are more frequently attrib-
utable to tumor disruption of the conductive apparatus of
the middle ear. Cisplatin can cause ototoxicity, especially
when administered following radiation of aural struc-
tures, as reported in children with brain tumors [17,18].
Statural growth failure is usually considered a result of
pituitary irradiation, and has been reported in many pa-
tients who received cranial irradiation for central nervous
system leukemia, brain tumor, or sarcoma in a juxtapi-
tuitary location [13,19–21]. However, not all patients
who receive pituitary irradiation in excess of 40 Gy be-
come deficient in growth hormone [21]. Direct irradia-
tion of the thyroid gland may cause chemical and some-
times clinical hypothyroidism; this is commonly reported
after irradiation for Hodgkin disease and should be
treated with thyroid hormone replacement [22]. Second-
ary thyroid cancer can also occur [22], but none has been
described in this series. Finally, the effects of combined-
modality management on facial structures [11,13] and
dentition can be serious and tend to be worse in young
patients, those with tumor infiltration of the masseter and
pterygoid muscles, and those treated with high doses of
radiation [23–25]. Trismus can be minimized by early
initiation of a preventative exercise program. Careful
dental evaluation can identify many alterations in denti-
tion that might not be obvious without appropriate dental
radiographs [23,24]. All children with RMS of the head
and neck should have pretreatment and follow-up exami-
nations of all head and neck structures, including the
teeth.
Problems with learning may develop in some patients
who receive whole-brain irradiation and intrathecal
medications, as is evident in this series. Children with
acute lymphoblastic leukemia who are treated with pro-
phylactic brain radiation using doses lower than those for
RMS/USS, with or without intrathecal methotrexate, are
more likely than their siblings to require special educa-
tion or a program for the learning-disabled. The risk is
also increased in those who receive 24 Gy rather than 18
Gy of radiation for leukemia [26].
370 Raney et al.
Second malignant neoplasms (SMN) have been re-
ported in patients treated on IRSG protocols, most fre-
quently osteogenic sarcoma [27] and acute myeloid leu-
kemia [28]. Other soft-tissue tumors and carcinomas in
the irradiated volume have also been noted. The four
SMNs reported here (one each of sarcoma, leukemia,
histiocytoma, and carcinoma) are similar to the larger
IRSG experience.
It is important to recognize that some of the compli-
cations we have described may be reduced or eliminated
by modern treatment approaches. Magnetic resonance
imaging can now provide a much better assessment of
tumor volume than could computed tomography, which
was the state of the art when many of these patients were
treated. In addition, conformal radiation therapy tech-
niques with multiple fields is increasingly available; this
methodology minimizes potential damage to nearby
structures and improves the ability to focus the radiation
beam on the target volume while protecting surrounding
normal tissues. Also, IRSG protocols since 1991 have
routinely omitted whole-brain radiotherapy for patients
with cranial parameningeal sarcoma; currently it is used
only for the rare patient who presents with malignant
cells in the spinal fluid. These recent IRSG protocols also
recommend annual assessment of growth, pubertal sta-
tus, and thyroid function, as well as ophthalmologic and
dental examinations of patients with sarcomas of the
head and neck; these provisions should permit a more
systematic assessment of late effects in the future.
All patients with sarcomas of the head and neck need
prolonged follow-up by a multidisciplinary team whose
members are focused on detection, prevention, and re-
mediation of possible sequelae [13,21]. Ideally, the team
should consist of a pediatric oncologist and radiation
oncologist, with access to pediatric specialists in endo-
crinology, ophthalmology, otolaryngology, dentistry, and
psychology. Abnormalities in any of the structures of the
head and neck should be noted at diagnosis and corrected
prior to treatment of the sarcoma, or as soon as possible
thereafter. Ototoxic drugs should be avoided, especially
in children who already have impaired hearing (e.g.,
those with middle-ear rhabdomyosarcoma). We no long-
er use cisplatin for initial treatment of children with rhab-
domyosarcoma, because efficacy was not demonstrated
in the randomized IRS-III trial [8] and because serious
ototoxicity occurred. Irradiation should be administered
using precise, localized fields to doses appropriate to
maximize local control while attempting to minimize in-
jury to structures within or near the irradiated volume.
The IRS-IV randomized comparison of conventional vs.
hyperfractionated radiotherapy may provide new data in
this regard [29]. Future treatment programs should be
designed to mitigate or avoid the known late effects of
therapy without compromising the likelihood of survival.
CONCLUSIONS
In summary, numerous sequelae affecting statural
growth, cosmetic appearance, dentition, and special
senses can occur after multimodality therapy for children
with nonorbital sarcoma of the head and neck. Some of
the problems can be alleviated by specific measures, af-
fording the survivors an acceptable quality of life. The
search is ongoing for better ways of managing these pa-
tients to maximize the likelihood of cure and minimize
the risk of adverse effects.
ACKNOWLEDGMENTS
We are grateful to Ms. Linda Tisch, Research Dosim-
etrist at the Quality Assurance Review Center, for help
with calculating the off-axis doses to the pituitary and
thyroid glands and the eye and to Mrs. M. Elizabeth
Buitron for excellent secretarial assistance. We are also
grateful to Dr. Richard Sposto and Ms. Sara Harper,
Betty Mulugeta, and Wendy Wong for assistance in re-
viewing the research records.
REFERENCES
1. Young JL Jr, Ries LG, Silverberg E, et al. Cancer incidence,
survival, and mortality for children younger than age 15 years.
Cancer 1986;58:598–602.
2. Sutow WW, Lindberg RD, Gehan EA, et al. Three-year relapse-
free survival rates in childhood rhabdomyosarcoma of the head
and neck: report from the Intergroup Rhabdomyosarcoma Study.
Cancer 1982;49:2217–2221.
3. Wharam M, Beltangady M, Hays D, et al. Localized orbital rhab-
domyosarcoma: an interim report of the Intergroup Rhabdomyo-
sarcoma Study Committee. Ophthalmology 1987;94:251–254.
4. Raney RB Jr, Tefft M, Newton WA, et al. Improved prognosis
with intensive treatment of children with cranial soft tissue sar-
comas arising in nonorbital parameningeal sites: a report from the
Intergroup Rhabdomyosarcoma Study. Cancer 1987;59:147–155.
5. Wharam MD Jr, Foulkes MA, Lawrence W Jr, et al. Soft tissue
sarcoma of the head and neck in childhood: nonorbital and non-
parameningeal sites. A report of the Intergroup Rhabdomyosar-
coma Study (IRS)-I. Cancer 1984;53:1016–1019.
6. Maurer HM, Beltangady M, Gehan EA, et al. The Intergroup
Rhabdomyosarcoma Study-I. Cancer 1988;61:209–220.
7. Maurer HM, Gehan EA, Beltangady M, et al. The Intergroup
Rhabdomyosarcoma Study-II. Cancer 1993;71:1904–1922.
8. Crist W, Gehan EA, Ragab AH, et al. The Third Intergroup Rhab-
domyosarcoma Study. J Clin Oncol 1995;13:610–630.
9. Heyn R, Ragab A, Raney RB Jr, et al. Late effects of therapy in
orbital rhabdomyosarcoma in children: a report from the Inter-
group Rhabdomyosarcoma Study. Cancer 1986;57:1738–1743.
10. Shimada H, Newton WA Jr, Soule EH, et al. Pathologic features
of extraosseous Ewing’s sarcoma: a report from the Intergroup
Rhabdomyosarcoma Study. Hum Pathol 1988;19:442–453.
11. Donaldson SS, Castro JR, Wilbur JR, et al. Rhabdomyosarcoma of
head and neck in children. Combination treatment by surgery,
irradiation, and chemotherapy. Cancer 1973;31:26–35.
12. Haik BG, Jereb B, Smith ME, et al. Radiation and chemotherapy
of parameningeal rhabdomyosarcoma involving the orbit. Oph-
thalmology 1986;93:1001–1009.
 Late Sequelae of Head/Neck Sarcoma in Childhood
13. Fromm M, Littman P, Raney RB, et al. Late effects after treatment
of twenty children with soft tissue sarcomas of the head and neck:
experience at a single institution with a review of the literature.
Cancer 1986;57:2070–2076.
14. Chan RC, Shukovsky LJ. Effects of irradiation on the eye. Radi-
ology 1976;120:673–675.
15. Abramson DH, Notis CM. Visual acuity after radiation for orbital
rhabdomyosarcoma. Am J Ophthalmol 1994;118:808–809.
16. Brown GC, Shields JA, Sanborn G, et al. Radiation retinopathy.
Ophthalmology 1982;89:1494–1501.
17. Baum ES, Gaynon P, Greenberg L, et al. Phase II trial of cisplatin
in refractory childhood cancer: Children’s Cancer Study Group
report. Cancer Treat Rep 1981;65:815–822.
18. McHaney VA, Thibadoux G, Hayes FA, et al. Hearing loss in
children receiving cisplatin chemotherapy. J Pediatr 1983;102:
314–317.
19. Shalet SM, Ogilvy-Stuart AL, Crowne EC, et al. Indications for
human growth hormone treatment of radiation-induced growth
hormone deficiency. In: Green DM, D’Angio GJ, editors. Late
effects of treatment for childhood cancer. New York: Wiley-Liss,
Inc.; 1992. p 71–79.
20. Sklar CA. Neuroendocrine complications of cancer therapy. In:
Schwartz CL, Hobbie WL, Constine LS, et al., editors. Survivors
of childhood cancer: assessment and management. Chicago:
Mosby-Year Book, Inc.; 1994. p 97–110.
21. Kao GD, Willi SM, Goldwein J. The sequellae of chemo-radiation
therapy for head and neck cancer in children: managing impaired
growth, development, and other side effects. Med Pediatr Oncol
1993;21:60–66.
371
22. Constine LS, Schwartz CL. The thyroid gland. In: Schwartz CL,
Hobbie WL, Constine LS, et al., editors. Survivors of childhood
cancer: assessment and management. Chicago: Mosby-Year
Book, Inc.; 1994. p 151–158.
23. Jaffe N, Toth BB, Hoar RE, et al. Dental and maxillofacial ab-
normalities in long-term survivors of childhood cancer: effects of
treatment with chemotherapy and radiation to head and neck. Pe-
diatrics 1984;73:816–823.
24. Kaste SC, Hopkins KP, Bowman LC. Dental abnormalities in
long-term survivors of head and neck rhabdomyosarcoma. Med
Pediatr Oncol 1995;25:96–101.
25. Chacko DC. Considerations in the diagnosis of radiation injury.
JAMA 1981;245:1255–1258.
26. Haupt R, Fears TR, Robison LL, et al. Educational attainment in
long-term survivors of childhood acute lymphoblastic leukemia.
JAMA 1994;272:1427–1432.
27. Heyn R, Haeberlen V, Newton WA, et al. Second malignant neo-
plasms in children treated for rhabdomyosarcoma. J Clin Oncol
1993;11:262–270.
28. Heyn R, Khan F, Ensign LG, et al. Acute myeloid leukemia in
patients treated for rhabdomyosarcoma with cyclophosphamide
and low-dose etoposide on Intergroup Rhabdomyosarcoma Study
III: an interim report. Med Pediatr Oncol 1994;23:99–106.
29. Donaldson SS, Asmar L, Breneman J, et al. Hyperfractionated
radiation in children with rhabdomyosarcoma—results of an In-
tergroup Rhabdomyosarcoma Pilot Study. Int J Radiat Oncol Biol
Phys 1995;32:903–911.