Treatment strategies for infants with malignant sacrococcygeal teratoma

Treatment By R.

Strategies for Infants With Malignant Sacrococcygeal Teratoma

Beverly Raney, Jr., Jane Chatten, Philip Littman, Patricia Jarrett, Louise Schnaufer, Harry Bishop, and Giulio J. D’Angio Philadelphia,

6 Twelve children with malignant sacrococcygeal teratoma containing embryonal carcinoma, were treated at the Children’s Hospital of Philadelphia between 1971 and 1980. Their ages at diagnosis ranged from 2 days to 23 mo; 8 of the 12 (67%) were girls. Five of the 12 patients presented with localized tumors which were grossly completely excised. Four received no further therapy, and all 4 recurred with histologically documented embryonal carcinoma. Despite subsequent treatment with radiation therapy (RJ) and chemotherapy (vincristine, actinomycin D. and cyclophosphamide, collectively called VAC, in all 4 plus adriamycin in 3. only 1 has survived free of disease, 8 yr from diagnosis. The other 3 died of tumor (2) or pneumonia after pulmonary RT (1). The fifth patient in this group received VAC with adriamycin (total dose, 350 mg/sq m) and died of autopsy-proven cardiotoxicity without tumor. The remaining 7 patients presented with either unresectable local tumor (3) or distant metastases (4). One of these 7 died 6 days after biopsy with massive liver metastases. The other 6 children were treated after operation with VAC (5) or vincristine and actinomycin D (1) chemotherapy, and 5 also received RT to the pelvis. One has survived free of disease at 6 yr after treatment with VAC and adriamycin and pelvic RJ, but the other 5 died of tumor (2) or of pneumonia after pulmonary RT (3). Surgery alone is inadequate for successful management of children with malignant sacrococcygeal teratoma. Chemotherapy with VAC, with or without adriamycin, can be effective when combined with radiation, but fatal pulmonary toxicity can result from such combined therapy. The optimal therapeutic program for children with malignant sacrococcygeal teratoma is still evolving.

Pennsylvania

combined

modality

treatment

using

surgery,

radiation therapy (RT),

and chemotherapy

infants with malignant

SCT

in 12

seen at the Chil-

dren’s Hospital of Philadelphia

(CHP).

MATERIALS AND METHODS Patients Twenty-eight

patients

between January

with XT

were referred

197 I and December

(43%) were malignant, age of the children

an average of

to CHP

1979. Twelve of the 28

I .3

cases per year. The

at diagnosis of malignant

SCT

ranged

from 2 days to 23 mo. with a median of 14 mo and a mean of

I 1 mo.

Eight of the 12 children (67%)

white.

No

congenital

patient

had a family

abnormalities

were female; all were

history of twins, and no

were noted on physical or radio-

graphic examinations.

Pathology Pathologic

materials

were available

for review in every

patient. Each child had embryonal carcinoma as the predominant type of malignant men.9.‘0 However,

benign tumor initially, carcinoma

tissue found in the tumor while the other

in the initial material.

10 had unequivocal

The malignant

the disease in the 2 patients with “benign” was documented

speci-

2 of the children were thought to have a

as follows. Patient

I

nature of

first specimens

(Table

1) was well

after excisional surgery at 2 days of age, but presented with biopsy-proven

embryonal

carcinoma

in endobronchial

pleural metastases at 2 yr of age. Additional stored primary

tumor showed a malignant

and

samples of her area in 1 of 22

sections, thus explaining the metastases. In patient 2, 5 large sections of the primary showed no malignant

tumor

removed

at day 2 of age

changes, but pure embryonal

carci-

noma was found 8 mos later in the specimen obtained at the

INDEX WORD: Malignant sacrococcygeal teratoma.

S

ACROCOCCYGEAL

TERATOMA

(SCT) is a rare neoplasm which primarily affects infants, and is 2-4 times more common in girls than in boys.‘-8 The great majority

of SCT

removed in the neonatal period are benign, but the likelihood

of malignant

degeneration

ad-

vances with age during the first several months of life.‘~5~s Simple surgical excision of the benign SCT is known to produce excellent results. However, management of patients with malignant SCT is more difficult. This report presents the results of

Journat of Pediatric Sur@?rv, Vol. 16, No. 4, Suppl. 1 (August), 198 1

From the Children’s Cancer Research Center, the Division of Oncology and Departments of Pathology and Surgery of the Children’s Hospital of Philadelphia, and the Departments of Pediatrics and Radiation Therapy, University of Pennsylvania School of Medicine, Philadelphia. Pa. Presented before the I I th Annual Meeting of the American Pediatric Surgical Association. Marco Island, Florida. May 7-10. 1980. Supported in part by Grant CA 14489 from the National Cancer Institute. Address reprint requests to Dr. R. B. Raney, Division of Oncology. ChildrenL Hospital of Philadelphia. 34th Street and Civic Center Boulevard, Philadelphia. Pa. 19104. o 1981 by Crune & Stratton, Inc. 0022-3468/81/1607~007%01.00/0

573

574

RANEY ET AL

Table 1. Malignant

Sacrococcygeal

1500

L""QS

4200

Pd”lS

0

Teratoma,

1971-1979

-

‘4000

Pd”6

‘2000

Lumbar

spme

L""QS

1200 ‘2000

Peh*

‘1200

LU”@

‘“AC

4

A&

0

tMet. Site, site of metastasis at diagnosis. SRadiation therapy and Chemotherapy are starred when used prospectwely after imtial diagnosis. I/V. vincristine; A, actlnomycln D; C, cyclophosphamide; Adr, adriamycin; HN,, nitrogen mustard.

time of local recurrence.

No retrospective examination

initial tumor was undertaken, Serum

markers

chorionic

such

gonadotrophin.

were not obtained counterparts

of her

as

alpha-fetoprotein.”

and

routinely

carcinoembryonic

in these children,

given

at

120P200

rad/day

received lung radiation

since no tissue was available. human

rad. given at 150P200

antigen

radiation

and their

Table

rad/day.

was administered

3-5

wk.

Thoracic

chemotherapy

and Clinical Grouping

patients

I200-.1600

or lumbar

spine

to 2 patients (nos. 7 and 12 in

over 3-4 wk. in an attempt to diminish

the effects of cord compression by vertebral

Surgery

Five

from

I) for a total of 4000 and 3000 rad respectively, given

at I50- 200 rad/day

were not sought histologically in the tissue.

over

in doses ranging

was given concurrently

tumor.

Usually

with radiation

thera-

PY. The patients were not approached surgically in a uniform manner.

As outlined

in Table

1. 5 patients (numbers

had no metastases at diagnosis, and surgery remove all visible tumor was accomplished patients

presented

with nonmetastatic

9-12)

presented

tumors

with distant

to

in each. Three which were

incompletely excised (patients 668), and 4 additional (patients

l-5)

sufficient

infants

metastases in lung

plus another site (3) or in a vertebral body

(1).

The patients were grouped by extent of disease at diagnosis and after

initial

surgery.

Those with grossly complete

excision were placed in Group disease were in Group

I. those with gross residual

II, and those with distant metastases

Chemotherapy vincristine,

Radiation

therapy

1 (no.

cis-platinum,

and nitrogen mustard in

Clinical Groups II and III (Table additional 3675 Rad)

in 5 patients

in

1) and subsequently in an

5. Doses ranged from 2000 to 5000 Rad (mean. in the 8 receiving radiation

to the primary

site,

I

coma Study were followed.” was used along with VAC to patient

though

No patient transient

cyclophosphamide

6

(collec-

Schedules

Rhabdomyosar-

In addition. adriamycin In general,

500 neutrophils

development

upward

escalation

severe

neutropenia

myelo-

thereafter

developed culture-proven

and adriamycin.

of

per mm”) led to

of subsequently administered

with

(Adr)

in 8 patients. Doses were adjusted

tolerance.

(under

I I).

(no.

similar to those employed in the Intergroup

tolerated.

in

6 in Table 1). and vinblastine, bleomycin.

suppressive agents, was used initially

operation

D and cyclophosphamide

tin D only in

reduction by 25%50’%

Therapy

initial

in the other 6. It consisted of

in IO patients, vincristine and actinomy-

severe neutropenia

Radiation

used after

actinomycin

tively called VAC)

according

at diagnosis were in Group 111.

was

patients and after recurrence

was common

Chemotherapy

as

septicemia. after

was given

for I to 2 yr or until recurrence, whichever occurred sooner.

MALIGNANT

SACROCOCCYGEAL

TERATOMA

RESULTS

The characteristics of the primary tumor, the dosage and volume of radiation therapy, the chemotherapy, the subsequent clinical course, and the survival duration are displayed in Table I. All of the primary tumors were predominantly presacral; the widest diameter in the 8 whose size was estimated varied from 3 to 20 cm (mean, IO cm). Four of the tumors were localized to the presacral region, I filled the pelvis but did not extend beyond it, 4 involved one or both buttocks at diagnosis and 3 extended to the retroperitoneal region. Four patients had metastases at diagnosis involving lung and inguinal nodes (I), lung plus liver and retroperitoneal lymph nodes (I), lung plus lumbar vertebral body (I), or lumbar vertebral body only (I). Following grossly complete excision 4 patients had no further treatment (patients I through 4 in Table I). The 2 children (nos. I and 2) among these 5 with SCT initially adjudged benign have been described above. They were treated with VAC plus Adr after relapse. Patient l’s chest lesions responded partially (50% shrinkage), but she ultimately died of lung and brain metastases without clinical evidence of recurrence at the primary site (no autopsy). Patient 2 did not respond favorably to drugs and radiation and died of progressive local disease. Another child whose tumor was completely excised (no. 3) developed lung metastases 43 wk from diagnosis and died of bilateral interstitial pneumonia of uncertain etiology, 4 mo after completing 1500 rad of bilateral lung radiation therapy (RT). Patient 4 developed a local recurrence which was excised at 30 wk; subsequent therapy included VAC plus pelvic RT, and she is well 8 yr from diagnosis with no evidence of tumor. Because of tumor recurrence in each of the first 4 patients, the fifth was given chemotherapy after excision of the SCT. VAC and adriamycin (total dose, 350 mg/sq m) were given for 13 mo beginning when she was 5 mo old. She died of sudden-onset congestive failure at 20 mo. Autopsy showed changes typical of adriamycin cardiotoxicity; no tumor was discerned grossly or microscopically. One (no. 6) of the 3 patients presenting with incompletely resected local disease received chemotherapy with 2 drugs and radiation to the primary tumor after operation. Despite this ther-

575

apy. lung metastases were detected 9 wk later, and 1600 rad were subsequently given to both lung fields. He died 2 mo later of pneumonitis attributed to the effects of combined actinomytin D and radiation. At autopsy there was extensive pulmonary fibrosis with only a few viable tumor cells seen in mediastinal lymph nodes, but not in the lungs; tumor was still present at the primary site and in paraaortic lymph nodes. Patient 7 was not treated until 5 wk after primary surgery elsewhere, when he developed spinal cord compression and was referred to the Children’s Hospital of Philadelphia. He was given radiation, VAC, and Adr. His disease responded partially, but he died 39 wk after diagnosis with widespread lung metastases and 2 bony metastases. Patient 8 was successfully treated after biopsy with pelvic RT (5000 rad) and VAC with Adr; she has no evidence of disease 6 yr later. All 4 patients presenting with metastases (numbers 9912) received chemotherapy after operation, and 3 also received radiation. Two of the three who received lung radiation (I 200 rad) developed pneumonia 6 mo later and died. One had pulmonary fibrosis and necrotic tumor (none viable) at autopsy. The other’s pneumonia was attributed to Pneumocystis carinii, although a contributing cause may have been pneumonitis resulting from combined therapy; unfortunately, no autopsy was performed. Patient 1 I was given drugs other than VAC because of massive liver disease; she died of liver failure and secondary coagulopathy 6 days after biopsy. Patient 12 had persistent, unresectable primary disease, although her lung metastases disappeared after VAC, reappeared but vanished again after a course of vinblastine, bleomycin, and cis-platinum, but returned despite lung radiation therapy, Adr, and methotrexate. She died of widespread tumor 58 wk after diagnosis. There are only 2 long-term, disease-free survivors out of the 12 infants (17%) in this series. Neither of them presented with detectable metastases at diagnosis. Four patients died with pneumonia 2 to 6 mo after pulmonary radiation. Two of these 4 children had autopsy evidence of interstitial pulmonary fibrosis attributed to the effects of combined therapy. An additional baby died of adriamycin cardiotoxicity after a relatively low cumulative dose (350 mg/sq m) and at

RANEY ET AL.

576

autopsy had no viable tumor. Five are dead of local (1) or metastatic (4) tumor.

DISCUSSION

The prognosis for infants with malignant sacrococcygeal teratoma is poor.‘,3-9 There were no survivors among the 21 consecutive patients reported by Chretien et al. in 1970.9 Radiation therapy and chemotherapy (actinomycin D, cyclophosphamide, methotrexate, daunomycin), produced transient responses in some patients, however, and the authors concluded that multimodal therapy should be employed in children with embryonal carcinoma arising in the sacrococcygeal region. Of interest is the fact that the patterns of metastases noted by Chretien et al. were quite similar to ours: lungs, vertebrae, and inguinal lymph nodes were most often affected, and less commonly the liver and mediastinunl.9 Others have supported the view that combined therapy should be used in infants with malignant XT, in view of the high likelihood of local recurrence, distant metastases, or both.8,‘3 Nearly every patient with malignant SCT who develops recurrent disease will die, usually within a year from initial diagnosisI and therefore an aggressive approach is justifiable. Recently, radiation therapy and various combinations of drugs have been employed in a prospective manner for 6 patients treated at Memorial Hospital between 1970 and 1978.” At the time of the report (June 1979), 4 of the 6 children were alive and free of disease, with 3 of the 4 off therapy. Two failed to respond completely. One was dead with unresponsive local disease despite 4000 rad and 6 drugs; the other was alive with unresectable pulmonary disease 18 months after chemotherapy and 1400 rad to the lungs.13 Investigators agree about the utility of chemotherapy and radiation therapy in the management of these children, since responses to drugs

and an occasional cure have been reported.“,‘3,‘s One patient with malignant SCT (no. 8 in our series) is free of disease 6 yr after receiving VAC, Adr, and pelvic RT following incomplete resection of local disease. None of the other 6 children given chemotherapy + RT prospectively after initial operation is alive; three died of causes that can be attributed at least in part to the effects of combined drugs and pulmonary radiation, I died of adriamycin cardiotoxicity, and 2 died of widespread tumor. On the other hand, use of drugs and RT for recurrent disease is usually unsuccessful also. Only I of 5 such patients is free of disease (no. 4); the others died of widespread tumor (3) or of pneumonia which was considered related to treatment. In conclusion, it is apparent that malignant XT can respond to multimodal management with RT plus VAC and Adr. The relatively high rate of fatal complications of therapy in this series (5112) indicates the difficulty of designing a tolerable, yet effective plan of treatment for these infants. Multiple drugs such as VAC and Adr may be useful, but caution should be used in giving adriamycin to babies,” and one should probably not exceed a total cumulative dose of 300 mg/sq m. Pulmonary irradiation should also be given carefully. A total dose of 1500 rad at 150 rad/day should not be exceeded. This dose of irradiation, when given along with multiple agent chemotherapy, is associated with low risk of significant morbidity.” However, if the daily dose of 150 rad is exceeded, or if additional irradiation is given to portions of the lung or mediastinum, the risk of developing severe pneumonitis increases significantly.‘x It is apparent that the optimum program of management for children with malignant sacrococcygeal teratoma still needs further definition. The major hindrances in designing future treatment schedules are the relative rarity of the disease and the fragility of its victims.

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MALIGNANT

SACROCOCCYGEAL TERATOMA

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