Results of Treatment of Malignant Germ Cell Tumors in 93 Children: A Report From the Childrens Cancer Study Group ByA.R. Ablin, M.D. Krailo, N.K.C. Ramsay, M.H. Malogolowkin, H. Isaacs, R.B. Raney, J. Adkins, D.M. Hays, D.R. Benjamin, J.L. Grosfeld, S.L. Leikin, M. Deutsch, and G.D. Hammond We report treatment results in 93 children entered on study from 1978 to 1984 with malignant germ cell tumors (MGCTs), excluding dysgerminoma and tumors of the testis or brain. The estimated 4-year survival and event-free survival (EFS) for all 93 patients were 54% and 49%, respectively. For 30 children with ovarian tumors, the estimated 4-year survival was 67%and EFS was 63%. For 63 children with nongonadal tumors, survival and EFS were 48% and 42%, respectively. The comparison of EFS between ovarian and nongonadal tumors was significant at P = .03. The treatment plan included a second-look surgical procedure after 18 weeks of chemotherapy. Over half of 36 patients evaluated as having a residual mass present

MALIGNANT

GERM cell tumors (MGCT)

occur in fewer than 300 children below the age of 15 years each year in the United States.' Before 1975, the results of the treatment of childhood MGCT with surgery or surgery followed by radiation therapy were poor. In 1965 Abell et al2

reported the median survival of eight patients with ovarian embryonal carcinoma to be 4 months: no

patient survived longer than 14 months. Similar 3 results were reported by Ein, and Huntington and

Bullock.4 In 1975, Smith and Rutledge5 reported on 20 patients between the ages of 7 and 38 years with a diagnosis of ovarian MGCT. Fifteen of

From the University of California, San Francisco;School of Medicine, University of Southern California, Los Angeles; Children'sHospitalof Los Angeles, Los Angeles, CA; University of Minnesota Medical Center, Minneapolis, MN; MD Anderson CancerCenter,Houston, TX; Children'sHospitalof Pittsburgh, Pittsburgh;Pittsburgh Presbyterian Hospital,Pittsburgh, PA; Children's Hospital and Medical Center, Seattle, WA; James Whitcomb Riley Hospital, Indiana University Medical Center, IN; and Children's NationalMedical Center, Washington, DC. Submitted October3, 1990; acceptedApril 11, 1991. Supported in part by a grant from the Division of Cancer Treatment, National Cancer Institute, National Institutes of Health, Departmentof Health andHuman Services. Address reprint requests to the Childrens Cancer Study Group, 440 E Huntington Dr, Suite 300, PO Box 60012, Arcadia, CA 91066-6012. © 1991 byAmencan Society of ClinicalOncology. 0732-183X/91/0910-0001$3.00/0

1782

immediately before second-look surgery had no malignant tumor after review of surgical specimens. Age greater than 11 years at diagnosis, incomplete removal of tumor at first surgery, and more than one structure or organ involved at diagnosis increased the risk for adverse event. The histologic subtype of the primary tumor was not related to outcome. Diagnosis was verified by independent pathologic review, and treatment was uniform. Seventeen percent of all registered patients (21 of 127) were excluded because of ineligible pathologic diagnoses; sixty percent (13 of 21) were immature teratomas. J Clin Oncol 9:1782-1792. o 1991 by American Society of ClinicalOncology.

those patients survived, with follow-up times ranging from 3 to 78 months. After initial operation, they received chemotherapy consisting of vincristine, dactinomycin, and cyclophosphamide. In 1976 Wollner et a16 reported that six of 10 children with ovarian MGCT treated with surgery, radiation therapy, and chemotherapy consisting of vincristine, dactinomycin, cyclophosphamide, and doxorubicin were alive 7 to 35 months from diagnosis. 8 7 Samuels et al in 1975 and Einhorn and Donahue

in 1977 reported that cisplatin-based regimens produced a 70% complete remission rate and a 55% long-term disease-free survival in the treatment of adults with testicular MGCT.

When this study was instituted, there was a need to build on the results of Wollner et al' and

Smith and Rutledge 5 in a larger group of children with MGCT. In addition, the results obtained with

cisplatin and bleomycin suggested that these agents might be alternated with vinblastine, dactinomycin, cyclophosphamide, and doxorubicin as an effective chemotherapy program for children with

MGCT. Therefore, the Childrens Cancer Study Group (CCSG) undertook a study with the hypothesis that two different and possibly noncrossresistant alternating regimens would improve the outcome for children with MGCT (CCG-861). Because there was no consensus regarding the

necessity for chemotherapy in all infants or children with immature teratomas or dysgerminomas

Journal of Clinical Oncology, Vol 9, No 10 (October), 1991: pp 1782-1792

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TREATMENT OF PEDIATRIC GERM CELL TUMORS or which children with MGCT at cranial or testicular sites require chemotherapy, these histologic types and sites were excluded. This report from the CCSG is the largest group of children yet described with specific MGCT who have had independent pathology review and chemotherapy administered in a prospective and uniform fashion.

1783

A VELBAN IV 6 5 mg/mr BLEOMYCIN 15p /M' 3d

p

SECOND SURGERY

CYTOXAN

CT

so600mg/M ACTINOMYCIN 015 mg/K x 5d

MIm

ADRIAMYCIN 40 mg/M I

tI

Ad

0

METHODS CCG-861 was opened for entry in February 1978 to patients with ovarian tumors containing embryonal carcinoma, endodermal sinus tumors, choriocarcinoma, or a mixture of these three elements. Patients with a mature or immature teratoma or dysgerminoma were ineligible. Patient eligibility was broadened in March 1979 to include tumors with embryonal carcinoma, endodermal sinus tumor, or choriocarcinoma occurring at any site except brain and testis. The study was closed to entry in April 1984. Patients were observed through June 1989. Patients under 21 years of age at diagnosis and without prior chemotherapy or radiation therapy were eligible. Informed consent was obtained before administration of chemotherapy. Initial chemotherapy consisted of two 9-week cycles of vinblastine, bleomycin, cisplatin, cyclophosphamide, dactinomycin, and doxorubicin (Fig 1). At week 18, a secondlook operation was recommended for all patients initially stage III or IV and for patients whose physicians suspected residual tumor either by imaging studies or by elevated serum levels of alpha-fetoprotein or p-subunit of human chorionic gonadotropin (Fig 1). Patients with residual disease that could not be completely resected at second operation and those who did not have a second operation but in whom imaging studies or biochemical studies demonstrated residual tumor received radiotherapy to sites of known or suspected tumor. The total administered dose and dose rate varied according to the volume irradiated. Patients requiring whole-abdominal irradiation for widespread intraabdominal dissemination were treated with 2,000 cGy at 140 to 150 cGy/d. In such patients, residual tumor in the pelvis and paraaortic nodes was treated with an additional 1,500 cGy at 150 cGy/d. If tumor was confined to the pelvis, then 4,000 cGy was administered to the pelvis at 150 to 160 cGy/d. If involved, the entire liver was treated with 2,500 cGy at 130 to 140 cGy/d. Maintenance chemotherapy was continued until 2 years from diagnosis. Cisplatin was discontinued after the third cycle (cumulative dose, 180 mg/m2 ) and bleomycin after the seventh cycle (cumulative dose, 315 mg/im2). Doxorubicin was stopped after six courses, at a total dose of 320 mg/m2, if the heart was included in the radiation field or after nine courses, at a total dose of 440 mg/m 2 , if there was no cardiac irradiation (Fig 1). Physical examination and peripheral blood counts were performed at study entry and every 3 weeks while the patient received therapy. Liver and kidney function studies and chest x-ray were performed every 6 weeks; appropriate

EM

CIS-PLATINUM 2 60 mg/M

3

6

B VLB-BLEO-PLAT-'-

VLB-BLEO

X1

9 WEEKS

-It--//

0s9 WKS --

I

I

18

21

VLB

X4

X4 0 9 WKS

CPM-ACTINO

X9 ADRIA----------X6'9

"--XRT-I

-....

I

SI

21

9 WKS

24

I

..

27

60

.



9699102

WEEKS

Fig 1. MGCT study CCG-861. (A) Initial therapy; (B)maintenance. VLB, vinblastine; BLEO, bleomycin; PLAT, cisplatin; CPM, cyclophosphamide; ACTINO, dactinomycin; ADRIA, doxorubicin; XRT, radiationtherapy. imaging studies and bone scans were done every 3 months for the first year and every 6 months for an additional 2 years. Other tests were performed at the discretion of the treating physician. Toxicity was graded on a scale of 1 to 4, with grade 4 defined as life-threatening. Specific limits for each toxicity grade depended on the organ system and patient's age (schedule of toxicity measures available on request from CCSG). If the absolute neutrophil count (ANC) fell below 1,000/ JL and the platelet count fell below 100,000/p.L, therapy was delayed until these counts recovered. Therapy was delayed for any other grade 3 or 4 toxicity until resolved. Causative agents were then administered at 50% of pretoxicity dose followed by increments of 25% until full dose was again achieved. Protocol therapy was terminated for any of the following reasons: recurrence of disease, progression of disease, death, major protocol violation, or loss to follow-up. Complete remission (CR) was defined as absence of tumor on physical exam, imaging, or marker studies. Partial remission (PR) was defined as a greater than 50% decrease in tumor size as measured by the product of the two greatest diameters of the tumor. The response had to persist for more than 1 month. Stable disease (SD) was less than PR but with no tumor growth, and progressive disease (PD) was considered any evidence of tumor growth. Staging of ovarian tumors was done according to the International Federation of Gynecology and Obstetrics (FIGO) criteria. Stage I is disease limited to one or both ovaries with the capsule intact. Peritoneal washings or fluid do not have tumor cells present. Stage II is disease in one or

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1784

ABLIN ET AL

both ovaries and beyond the ovarian capsule. No metastases are present at any other site in the abdomen. Peritoneal washings or fluid do not have tumor cells present. Stage III disease involves one or both ovaries, with tumor present in the retroperitoneal lymph nodes or other abdominal sites or tumor cells present in the peritoneal fluid. Stage IV is malignant disease present outside the abdominal cavity or within the liver parenchyma. All patients were also assessed retrospectively for extent of disease at diagnosis. Patients were classified into one of two categories: (1) only one organ or structure involved by malignant disease (localized), and (2) disseminated spread (disseminated). Ovarian patients with FIGO stage I or II disease were classified as localized; patients with FIGO stage III or IV disease were classified as disseminated. Nongonadal tumor patients were segregated into one of the two groups by one of us (N.K.C.R.) according to the pretreatment disease evaluation data reported by the patient's physician. The analyses were restricted to eligible patients who, upon review of histologic material, were considered to have at least one of the following histologies present in the tumor: embryonal carcinoma, endodermal sinus tumor, or choriocarcinoma. Event-free survival (EFS) was defined as the time from the initial surgical procedure until recurrence of disease, progression of disease, death, or last contact. A patient who was alive and without progression of disease at last contact was considered to be without event at that date; in all other cases, an event was considered to have occurred. Survival was defined as the time from the surgical procedure, which confirmed the malignancy, until death or last contact. Death, regardless of cause, was considered a treatment failure. Plots of the estimated survival functions were constructed by the method of Kaplan and Meier.' Treatment comparisons and univariate prognostic factor evaluations for either outcome measure, survival or EFS, were performed by means of the log-rank test.9 Some characteristics examined were common to all patients, regardless of site or primary tumor. The prognostic significance of several characteristics common to all patients was assessed by the stratified log-rank test across two groups defined as ovarian and nongonadal tumors. The independent prognostic significance of selected factors was assessed by stepwise proportional hazards regression.' Characteristics that were not relevant to both ovarian and nongonadal patients were not considered in the regression model. Comparisons of outcome after planned second-look surgery included only patients who remained event-free until at least the 18-week evaluation. Outcome for patients who had second-look surgery was measured from the date of surgery and for those patients who did not have surgery, from week 18, the date of the planned surgery.

RESULTS PatientEntry One hundred twenty-seven patients were registered. Thirty-four were not eligible: 21 for ineligible diagnosis, eight because of treatment delays of

3 months or more from diagnosis or prior treatment with radiation, and five because no tissue was available for review (Table 1). Of the 93 eligible patients, 63 had nongonadal tumors and 30 had ovarian tumors. PatientCharacteristicsat Study Entry

Over 70% of patients with ovarian tumors were 10 years or older at diagnosis (Table 2). In contrast, over 70% of patients with nongonadal tumors were 2 years or younger and were more likely to be females than males (77% v 31%; P < .01). Patients with ovarian tumors more often had no detectable tumor remaining after the initial surgical procedure than did nongonadal tumor patients (73% v 13%, P < .01). Presence of metastases at diagnosis was not associated with

any particular histologic type. Most patients with nongonadal tumors entered on this study had primary tumors of the sacrum or coccyx (Table 2). The next most frequent primary site was the mediastinum. In patients 2 years of age or less at diagnosis, sacrococcygeal tumors occurred significantly more often than did tumors of other sites (70% v 30%, P = .01). The primary site of the tumor in seven of eight nongonadal tumor patients 11 years of age or older was the mediastinum. When ovarian and nongonadal tumors were

compared with respect to histologic makeup, each showed similar proportions of the three tumor types eligible in this study. However, patients with ovarian tumors more often had dysgerminoma as a component of their tumor than did patients with

nongonadal tumors (50% v 24%, P = .02). Females were more likely to have embryonal carcinoma detected than males (18% v 2%, P = .05). None of the sacrococcygeal tumors in patients of Table 1. Registration and Reasons for Ineligibility of Patients Entered on CCG-861 Characteristic

N

Registered Not eligible Pathology Immature teratoma Rhabdomyosarcoma Dysgerminoma Wilms' tumor Small-cell tumor Adenocarcinoma Prior treatment or treatment delay No material available for review Eligible

127 34 21 13 3 2 1 1 1 8 5 93

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TREATMENT OF PEDIATRIC GERM CELL TUMORS

1785

Table 2. Characteristics of Patients Entered on CCG-861

reported. In four of the 93 assessable patients (4%), echocardiograms or multigated nucleide scans were sufficiently abnormal to stop doxorubicin. No clinical cases of cardiac failure were reported. Therapy was otherwise administered as described by the protocol.

Characteristic

Age (years) S1 2 3-9 10-11 12-13 14+ Sex Male Female Histology Embryonal carcinoma Endodermal sinus tumor Choriocarcinoma Mixed, no teratoma Teratoma and embryonal carcinoma Teratoma and endodermal sinus Mixed with teratoma Primary site of tumor Sacrum or coccyx Mediastinum Vagina Retroperitoneum Omentum Hernia sac Cervix-uterus Buttock Unknown

Nongonadal (n = 63)

All (n = 93)

0 0 8 7 6 9

27 20 8 0 1 7

27 20 16 7 7 16

30

22 41

22 71

1 10 1 8

2 30 3 10

3 40 4 18

1

5

6

0 9

1 12

1 21

37 17 2 1 1 1 1 1 2

37 17 2 1 1 1 1 1 2

Ovarian (n = 30)

this group contained choriocarcinoma. Patients 2 years or less at diagnosis were more likely to have an endodermal sinus as a component of their tumor than older patients (89% v 50%, P < .01). Of 17 patients with mediastinal germ cell tumors, nine were males and eight were females.

Survival and EFS The 4-year survival and EFS for all 93 patients were 54% and 49%, respectively (Fig 2). There were four deaths among patients observed for 3 years or more, and five adverse events among patients observed for more than 2 years, indicating that late treatment failures occur. The estimated 4-year survival and EFS for patients with ovarian tumors were 67% and 63%, respectively; for patients with nongonadal tumors, 48% and 42%, respectively (Fig 3). The comparison of EFS between ovarian and nongonadal tumor sites was significant (P = .03). Three patients died without evidence of progressive disease. One patient developed chronic myelogenous leukemia 39 months after completion of chemotherapy. No radiation therapy had been given. One patient died of probable doxorubicin cardiomyopathy after 360 mg/m 2 of doxorubicin and 2 months after completion of chemotherapy. The cause of death was not reported for one patient. Table 3 lists the average failure rate in events per person-year of follow-up at various times since study entry. In only two of 93 patients was there treatment failure during the first 18 weeks (average failure rate, 0.063 events/person-year). In the next two 18-week intervals, 14 and 11 patients, respectively, experienced treatment failure (fail-

Toxicity

00uu

Grade 3 hematologic toxicity (defined by one or more of the following conditions: WBC count 1 to 1.9 x 103/ iL, platelet count 25 to 49 x 103/ ýL, or ANC 0.5 to 0.9 x 103/pL) occurred in 29 of 553 (5%) courses and grade 4 hematologic toxicity (defined by one or more of the following condi3

tions: WBC count < 1 x 10 /pL, platelet count < 25 x 10 3 /pL, or ANC < 0.5 x 10 3 / pL) in 20

of 553 (4%). Pulmonary function tests were recorded 82 times, and in 12 of them, some abnormality of function was recorded. Investigators felt changes were sufficient to discontinue bleomycin in seven patients. No deaths or clinical impairment, secondary to pulmonary insufficiency, were

075 L

050 o n

025

0 00

Fig 2. Outcome for all eligible patients: -, EFS. Bars represent 1 SE.

survival; ---- ,

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1786

ABLIN ET AL

In

075

L 0 50

a

025

0 00 Years Fig 3. EFS by tumor site: -, nadal (n = 63). P = .03.

ovarian (n = 30); ----., nongo-

ure rates, 0.48 events/person-year and 0.49 events/ person-year, respectively). CharacteristicsPrognosticofAdverse Event Nongonadal site (Fig 3), age greater than 11 years at diagnosis (Fig 4), tumor in more than one organ or structure, and tumor not completely removed at the time of original surgery were predictive of increased risk of adverse event (Table 4). Histologic subtype and presence of metastases at diagnosis were not significantly associated with the risk of an adverse event. In this study, prognosis was not well correlated with the FIGO staging system, which is based on findings at the initial surgery. Extent of Disease When all patients were compared relative to involvement of one structure or organ, or more than one structure or organ, there was a significant relationship with EFS (P = .01; Table 4). The estimated 4-year survival for patients with nongonadal tumors whose disease was confined to one structure or organ was 70%. Extent of disease as measured by presence or absence of metastases was not related to EFS (P = .54; Table 4). Patients with ovarian tumors with maximal di-

mension greater than 16 cm have a poorer outcome than patients with tumors less than 16 cm (P = .04). Intraoperative spillage was not related to EFS (P = .52). Ovarian patients who were not able to have complete removal of all tumor at the original operation were more likely to have a subsequent adverse event than those who were tumor-free after this surgery (P = .08; Table 4). When patients with nongonadal disease were compared as metastatic versus nonmetastatic, there was no significant association with EFS (P = .90; Table 4). Patients with nongonadal tumors who did not have complete removal of their tumor at original operation were almost eight times more likely to have a subsequent adverse event than those who were tumor-free after this surgery. Although patients with microscopic residual disease were at slightly less risk for adverse event when compared with patients who had gross residual disease after initial surgery, the difference was not significant at the .05 level (Table 4). Other Factors No significant association between site of primary nongonadal tumor and outcome was noted. There was no relationship between sex and outcome among the nongonadal tumor patients. Four factors were assessed for their independent prognostic significance for adverse event: (1) site of tumor; (2) extent of tumor before initial operation; (3) age at diagnosis; and (4) extent of tumor resection at initial operation. All factors were independently significant at the .05 level (Table 5). 100

a,

075 dL •LL _U_•~ JI~~.U~~~~ ..

L O C

-- -..----

050

O a O a

025

-

Table 3. Average Failure Rate by Time Since Study Entry No. of Weeks Since Study Entry

No. of Person-Years of Follow-Up

No. of Failures

Failure Rate (events/person-year)

1-18 19-36 37-54

31.6 29.2 22.4

2 14 11

0.063 0.48 0.49

0 00 (

I

I

I

I

I

I

I

1

2

3

4

5

6

7

I

8 9 Years

10

Fig 4. Survival after 18-week evaluation by presence of disease after planned date of surgical intervention: -, present (n = 23); ---- , absent (n = 52). P= .0001.

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1787

TREATMENT OF PEDIATRIC GERM CELL TUMORS Table 4. Relationship of Various Factors With Relative Risk for Adverse Event Ovarian n

Relative Risk

8 22

1 11

10 20

2 10

8 22 8 22

Characteristic Age group (years) •: 10 11+ Extent of disease Confined to 1 structure or organ Disseminated spread Amount of tumor removed at first surgery Incomplete Complete Metastatic disease present Yes No Amount of residual tumor after initial surgery Microscopic Gross Incomplete data

Tumor location Sacrum or coccyx Mediastinum Other

Nongonadal

No. of Events

P*

n

1.0 5.5

.06

55 8

31 6

1.0 1.9

.13

1.0 1.8

.02

1.0 3.0

.13

21 42

8 29

1.0 2.3

.03

1.0 2.5

.01

5 7

1.0 0.38

.08

55 8

36 1

1.0 0.13

.01

1.0 0.39

.003

5 7

1.0 0.40

.10

22 41

13 24

1.0 1.1

.90

1.0 0.83

.54

-

6 45

2 31

1.0 3.1

.10

-

-

-

-

-

-

-

-

-

2

-

37 17 9

-

23 11 3

Relative Risk

Adiustedt

No. of Events

P*

Pt

-

-

1.0 1.4 0.45

Relative Riskl

.19

-

*P value associated with log-rank test restricted to the stratum. tAdjustment accomplished by stratification on the basis of tumor site. *From adjusted log-rank test. §Nongonadal patients only.

Evaluation at 18 Weeks Before Possible Second Surgery Of the 93 eligible patients, two had disease progression before the 18-week evaluation and four could not be evaluated for response because of insufficient data. Eighty-seven patients were evaluated for response after 18 weeks of chemotherapy but before second surgery. There were 41 CRs (47%), 38 PRs (44%), and eight (9%) either SDs or PDs. Of all 87 patients, 29 had ovarian tumors and 28 responded: 16 (55%) CRs and 12 (42%) PRs. Fifty-eight of the 87 had nongonadal tumors, 51 of which responded: 25 (43%) CRs and 26 (45%) PRs. Thirty-four patients did not go on to a second surgical procedure. At presurgical evaluation, 10 had no evidence of disease, six had unresectable disease, two refused operation, and 16 had no reason given. Findingsat Second Surgery Twenty-one patients evaluated as CRs by normal imaging and marker studies and 36 patients evaluated as PRs had a second operation after the initial course of chemotherapy. Three of the 21

patients (14%) in CR were found to have residual malignant tumor. Twenty-two of the 36 patients (61%) in PR had no evidence of malignant disease in the material removed at the second operation. However, two of the 22 had elevation of alpha-fetoprotein. Both patients later exhibited recurrent disease and eventually died of progressive disease. Of the 14 patients with confirmed active disease at the time of second surgery, four had all apparent tumor removed. Effects ofRadiation Therapy As described in Methods, 17 patients received radiation therapy because of persistent tumor after 18 weeks of chemotherapy. Six of these 17-four with endodermal sinus tumors and two with mixed tumors-are long-term survivors. Only one of the six had metastatic disease at diagnosis, to the eighth thoracic vertebra and lung, but received radiation therapy only to the bone, and not to the lungs. The lungs cleared with chemotherapy alone and the bone involvement has not recurred after 11 years and 5 months. The sites of

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ABLIN ET AL

1788 Table 5. Assessment of Independent Prognostic Significance for EFS of Various Patient Characteristics Candidate Prognostic Factor

Tumor site Ovarian Nongonadal Extent of disease Confined to 1 structure or organ Disseminated spread Amount of tumor removed at first surgery Complete Incomplete Age group (years) •< 10 11+

Assessed as Independently Prognostic

Yes

Yes

Yes

Yes

Relative Risk*

95% Confidence Interval*

1.0 4.0

1.4-11

Pt

.011

.031

1.0 2.3

1.0-5.2

1.0 2.6

1.1-6.4

1.0 4.3

1.7-11

.038

.0021

*Taken from the regression model with all four factors. tP value associated with the test of hypothesis that the factor is not predictive of risk for adverse event when the other three factors are included in the regression model.

primary tumor were sacrococcyx, two cases; retroperitoneum, one case; hernia sac, one case; mediastinum, one case; and ovary, one case. Radiation treatment in 10 of the 17 patients failed in the field of radiation, either to the primary tumor or to the metastases: six had endodermal sinus tumors, three had mixed MGCT, and one had choriocarcinoma. The primary site of failure in all seven sacrococcygeal tumors was in the initial site of tumor. Three of these patients had disease recurrence in bone, lung, and paratracheal nodes as well. Treatment also failed in the sites of radiation therapy in two patients with mediastinal tumors and one with ovarian tumor. Outcome After Date of PlannedSecond Surgery Data were available on 75 patients after the planned date of the second operation, 59 of whom had the second operation and 16 in whom confirmation was based on physical examination, imaging studies, and tumor markers. Fifty-two patients were classified as having no evidence of disease: 10 had normal tumor markers and imaging studies at 18 weeks and did not have second surgery; 38 had second surgery and were found to have no disease; and four had disease that was completely removed. Twenty-three patients were classified as having evidence of residual disease: six had pre-

sumed unresectable tumor based on imaging and marker studies and did not have second surgery; 17 had second surgery and had pathologically confirmed residual disease after the procedure. Marker data were not available for these patients. The 4-year survival of patients in CR and in PR after the date of planned second surgery was 73% and 28%, respectively (P < .01; Fig 4). There were 31 patients judged to be in CR at the pre-second surgery evaluation. There was no difference in survival whether or not the second operation was performed (P = .70; Fig 5). Risk for death or adverse event were related to the findings at the 18-week presurgery evaluation. Patients with positive markers and scans were at greatest risk, those patients with one positive and one negative marker or scan were at intermediate risk, and those with negative markers and scans were at least risk regardless of outcome measure considered. However, negative markers and scans at the 18-week presurgical evaluation still were associated with considerable risks for adverse event or death, as 11 of 33 patients experienced an adverse event, and nine of those have died. Of 46 patients who had tumor progression, 90% died within 2 years of progression. The median survival for this group of patients was 9 months. No factor was specifically associated with risk for death subsequent to disease progression. DISCUSSION There is evidence of effectiveness for the chemotherapy. After the initial operation and before any 100

a,

075

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050

i

\'-----;,

o a o a

025

0 00

E

I

' I

I

I

r

4

5

6

1

7

9 8 Years

10

Fig 5. Survival after 18-week evaluation by performance of second surgery. Patients judged free of disease before planned surgical intervention only: -, yes (n = 21); ---- , no (n= 10). P =.70.

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TREATMENT OF PEDIATRIC GERM CELL TUMORS

chemotherapy, only 30 of the 93 patients (32%) were tumor-free, 33 (36%) had local residual disease, and 30 (32%) had metastatic disease present. At evaluation after 18 weeks of chemotherapy and before planned second surgery, 41 of 87 children (47%) were considered to be in CR and an additional 38 (44%) showed a PR for a total response rate of 91%. Although effective, this regimen possibly lacks the necessary intensity to achieve optimum results. This may be the case for cisplatin in particular. The average failure rate during the first 18 weeks of treatment was approximately one sixth as large as in each of the next two 18-week intervals (Table 3). Our patients received only three courses of cisplatin at 60 mg/m 2 in the first 20 weeks after which it was discontinued. Most probably, this was suboptimal cisplatin therapy and accounts in part for a modest survival rate. Results in this study have not been as good as those now being reported for children treated with cisplatin-based regimens."' 13 When this study was started, the best results reported were with either vincristine, cyclophosphamide, dactinomycin, and doxorubicin regimens or with vinblastine, bleomycin, and cisplatin.8 These two effective, noncrossresistant regimens were combined with the hope that alternating them would result in greater tumor-cell kill with lesser chance for development of resistant tumor-cell lines than when either was used alone.14 Green et a115 subsequently used two different noncrossresistant regimens in four patients, but instead of alternating them in each cycle, they used one regimen for induction and the other for maintenance. Although the total number of patients was small and follow-up for two patients was short, their results were encouraging. However, the anticipated high disease-free survival and survival rates in our study were not achieved, perhaps because one of the regimens may be less effective than the other, resulting in less frequent and less intensive administration of the more effective regimen. It may be postulated that the inclusion of cyclophosphamide, dactinomycin, and doxorubicin lengthened the intervals between the probably more effective vinblastine, bleomycin, and cisplatin courses. Current and future studies should evaluate higher doses of cisplatin than given in our study and avoid the use of agents that delay courses of cisplatin-based therapy. There is no evidence in our toxicity data

1789 that indicates such treatment would not be possible. Patients with ovarian tumors were at significantly reduced risk for adverse event when compared with patients with nongonadal tumors (63% v 42% EFS, P = .03; see Fig 3). However, since only eight of 63 (12%) of patients with nongonadal tumors had their disease completely resected after the initial surgery, compared with 22 of 30 (73%) patients with ovarian tumors, completeness of tumor resection may account for the difference in risk. Comparison of the evaluation before secondlook operation with the findings at surgery permits some observations on the validity of the evaluative procedure. When both the imaging studies and the markers were normal, those findings were falsely negative in three of 21 patients (14%). More striking were the frequent false-positive presurgical evaluations. In 67% of patients in whom tumor was judged to be present or possibly present preoperatively by imaging studies, none was found on review of surgical specimens removed at second operation. The imaging studies were more likely to be misleading since two patients with elevated alpha-fetoprotein and normal imaging studies later went on to develop recurrence and died with PD. Although the numbers were small, when the outcome of 10 patients who were judged to be free of tumor at pre-second-surgery evaluation and did not have this procedure was compared with the 21 patients who also were judged to be tumor-free but had a second surgical procedure, there was no significant difference. This suggests that, for patients in CR after 18 weeks of chemotherapy, a second-look procedure may not be warranted. The study design does not permit an evaluation of the effectiveness of radiation therapy. Patients who failed to respond completely to chemotherapy and surgery were the only ones to receive radiation therapy so that there was a bias in the selection for patients receiving radiation. They probably represented a group of patients at high risk for relapse. Those patients continued to receive chemotherapy as well, making it impossible to determine whether the long-term survival reports in the six of 17 patients were because of radiation or continued chemotherapy. It is possible, however, that radiation therapy may play a beneficial role in the treatment of both ovarian and nongonadal malignant germ cell tumors, but a definitive role is not

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established in this study. Our results are similar to those reported in adults by Kersh et al' 6 who reported local control in only four of 18 nonseminomatous extragonadal tumors. In adults, where seminomatous tumors are much more common than in children, 22 of 26 patients with seminomatous tumors responded to radiation therapy. In children this experience is found only in CNS tumors where dysgerminomas can be successfully treated with radiation therapy without chemotherapy.17,18

The reasons for exclusion of 34 of 127 registered patients are addressed to understand the patient population studied. Over 60% of the exclusions (21 of 34) were patients registered with a noneligible pathologic diagnosis as determined by the review pathologist. This was due to either a frank disagreement by the referee pathologist with the local institutional pathologist or confusion at the local institutional level as to which patients were eligible for this study. The most common tumors that were excluded were immature teratomas (13 of 22); 11 of 13 were in the ovary. Not all immature teratomas in children are malignant or necessarily require chemotherapy."9 Inclusion of such patients could skew our results to be falsely favorable to the therapeutic program. The outcome of children with immature teratomas is unresolved and must await a study whose entry includes patients with immature teratoma. Difficulty in the recognition of rare germ cell tumors is also underscored by the fact that eight other pathologic diagnoses were mistaken for one of the eligible MCGT (Table 1). This emphasizes the need for critical attention to the adequacy of pathologic review when evaluating results in studies of MGCT in children. Selected MGCTs were also excluded, since the role for chemotherapy had not been established for these tumors. Localized testicular tumors in infants and young children are often responsive20 to surgery alone and require no further therapy. ,21 Germ cell tumors of the brain were excluded because they are sometimes treated without biopsy and often respond to radiation therapy without chemotherapy. 22 Dysgerminomas have been shown to be successfully treated by surgery and radiation, making entry onto a study evaluating the effectiveness of chemotherapy inappropriate.' The patients eligible for this study all had aggres-

sive MGCT, which would not be expected to respond, except briefly, to surgery and/or radiation without chemotherapy. Comparison with other reports of children, which include tumors at the sites or with pathologic types that we have excluded, is therefore difficult and must be done with caution. Brodeur et a124 reported a 42% 5-year estimated survival for 57 MCGT patients admitted to St Jude Children's Research Hospital between 1962 and 1979. Four patients with dysgerminoma, 11 with immature teratoma, and 10 with testicular disease were included. These histologic types, as well as the testicular site, were eliminated from our study since some patients with these tumors may have a better prognosis and, perhaps, no need for chemotherapy. Therefore, comparisons are difficult, but our results are probably improved over Brodeur et al. Results in our study are similar to those reported by Flamant et a12 from Villejuif, France, and Buenos Aires, Argentina, on 35 children with nonseminomatous stage III and IV MGCT. The chemotherapy used in that study was similar to that in CCG-861 except for the use of methotrexate in some patients and vincristine instead of vinblastine. Doses and schedules, although not the same, were also similar. Comparison is again difficult because of differences in site and stage. Their results indicate a 25-month survival of 63%; our results at 25 months are 68%. Late recurrences are common to both studies. Our experience confirms much of that which was reported in the review of 89 cases of childhood endodermal sinus tumors and embryonal carcinoma from the Pediatric Oncology Group.26 We also found that there was no prognostic significance to the histologic type of germ cell tumor, that MGCTs occur with similar frequency in males and females, and that tumor site was an important prognostic factor for outcome. Again, the inclusion of testicular sites in their study and its limitation to endodermal sinus and embryonal carcinoma pathologic types makes overall outcome comparisons impossible. Germ cell tumors are among the potentially curable malignancies. However, further modifications in therapeutic programs, especially as used for children, are necessary before we approach the results reported in large series of adults at gonadal sites.

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TREATMENT OF PEDIATRIC GERM CELL TUMORS APPENDIX Principal Investigators, Childrens Cancer Study Group Institution

Investigator

GrantNo.

Group Operations Office, University of Southern California, Comprehensive Cancer Center, Los Angeles, CA

Denman Hammond, MD John Weiner, DrPH Harland Sather, PhD Richard Sposto, PhD Mark Krailo, PhD Jonathan Buckley, MBBS, PhD Madeline Bauer, PhD Raymond Hutchinson, MD

CA 13539

Arthur Ablin, MD

CA 17829

Ronald Chard, MD

CA 10382

Susan Shurin, MD

CA 20320

Gregory Reaman, MD

CA 03888

Edward Baum, MD

CA 07431

Jorge Ortega, MD

CA 02649

Frederick Ruymann, MD

CA 03750

Sergio Piomelli, MD Vincent Albo, MD

CA 03526 CA 36015

John Lukens, MD

CA 26270

Robert Neerhout, MD

CA 26044

William Woods, MD

CA 07306

Thomas Williams, MD

CA 36004

Anna Meadows, MD

CA 11796

University of Michigan Medical Center, Ann Arbor, MI University of California Medical Center, San Francisco, CA Children's Hospital and Medical Center, Seattle, WA Rainbow Babies and Children's Hospital, Cleveland, OH Children's Hospital National Medical Center, Washington, DC Children's Memorial Hospital, Chicago, IL Children's Hospital of Los Angeles, Los Angeles, CA Children's Hospital of Columbus, Columbus, OH Babies Hospital, New York, NY Children's Hospital of Pittsburgh, Pittsburgh, PA Vanderbilt University School of Medicine, Nashville, TN Doernbecher Memorial Hospital for Children, Portland, OR University of Minnesota Health Sciences Center, Minneapolis, MN University of Texas Health Sciences Center, San Antonio, TX Children's Hospital of Philadelphia, Philadelphia, PA Memorial Sloan-Kettering Cancer Center, New York, NY James Whitcomb Riley Hospital for Children, Indianapolis, IN University of British Columbia, Vancouver, Canada Children's Hospital Medical Center, Cincinnati, OH Harbor/UCLA and Miller Children's Medical Center, Torrance and Long Beach, CA University of Iowa Hospitals and Clinic, Iowa City, IA Children's Hospital of Denver, Denver, CO Mayo Clinic, Rochester, MI Izaak Walton Killam Hospital for Children, Halifax, Canada

CA 02971

Peter Steinherz, MD Robert Weetman, MD

CA 13809

Paul Rogers, MD

CA 29013

Beatrice Lampkin, MD

CA 26126

Jerry Finklestein, MD

CA 14560

Raymond Tannous, MD

CA 29314

David Tubergen, MD Gerald Gilchrist, MD Allan Pyesmany, MD

CA 28851 CA 28882

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childhood and adolescence: Tumors of germ cell origin. Am J Obstet Gynecol 92:1059-1081, 1965 3. Ein SH: Malignant ovarian tumors in children. J Pediatr Surg 8:539-542, 1973

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4. Huntington RW, Bullock WK: Yolk sac tumors of the ovary. Cancer 25:1357-1367, 1970 5. Smith JQ, Rutledge F: Advances in chemotherapy for gynecologic cancer. Cancer 36:669-674, 1975 6. Wollner N, Exelby P, Woodruff J, et al: Malignant ovarian tumors in childhood: Prognosis in relationship to initial therapy. Cancer 37:1953-1964, 1976 7. Samuels M, Johnson D, Holoye P: Continuous intravenous bleomycin therapy with vinblastine in stage III testicular neoplasia. Cancer Chemother Rep 59:563-570, 1975 8. Einhorn L, Donohue J: Cis-diaminedichloroplatinum, vinblastine and bleomycin combination chemotherapy in disseminated testicular cancer. Ann Intern Med 87:293-298, 1977 9. Kalbfleisch JD, Prentice RL: The statistical analysis of failure time data. New York, NY, Wiley, 1980 10. Pinkerton CR, Pritchard J, Spitz J: High complete response rate in children with advanced germ cell tumors using cisplatin containing combination chemotherapy. J Clin Oncol 4:194-200, 1986 11. Pinkerton CR, McElwain T, Horwich A, et al: Carboplatin (JM8), VP-16, bleomycin (JEB) in children with malignant germ cell tumors (MGCT). Med Pediatr Oncol 15:296-297, 1987 12. Gobel U, Bamberg M, Haas RJ, et al: Non-testicular germ cell tumors: Analysis of the therapy study MAKEI 83/86 and protocol changes for the follow-up study. Klin Padiatr 201:247-260, 1989 13. Mann JR, Pearson D, Barrett A, et al: Results of the United Kingdom Children's Cancer Study Group's malignant germ cell tumor studies. Cancer 63:1657-1667, 1989 14. Goldie JH, Coldman AJ: A mathematical model for relating the drug sensitivity of tumors to the spontaneous mutation rate. Cancer Treat Rep 63:1727-1733, 1979 15. Green DM, Brecher ML, Grossi M, et al: The use of different induction and maintenance chemotherapy regi-

mens for the treatment of advance yolk sac tumors. J Clin Oncol 1:111-116, 1983 16. Kersh CR, Constable WC, Hahn SS, et al: Primary malignant extra gonadal germ cell tumors: Analysis of the effect of radiotherapy. Cancer 65:2681-2685, 1990 17. Legido A, Packer RJ, Sutton LN, et al: Suprasellar germinomas in childhood: A reappraisal. Cancer 63:340344,1989 18. Gobel U, Bamberg M, Bodach V, et al: Intracranial germ cell tumors: Analysis of protocol MAKEI 83/86 and protocol changes for the following study. Klin Padiatr 201:261-268, 1989 19. Malogolowkin MH, Ortega JA, Krailo MD, et al: Immature teratomas: Identification of patients at risk for malignant recurrence. J Natl Cancer Inst 81:870-874, 1989 20. Peckham MJ, Barrett A, Husband JE, et al: Orchiectomy alone in testicular stage I non-seminomatous germ cell tumors of the testis. J Clin Oncol 3:326-335, 1985 21. Fernandes ET, Etcubanas E, Rao BN, et al: Two decades of experience with testicular tumors in children at St. Jude Children's Research Hospital. J Pediatr Surg 24:677-682, 1989 22. Jennings M, Gelman R, Hochberg: Intracranial germ cell tumors: Natural history and pathogenesis. J Neurosurg 63:155-167, 1985 23. Weinblatt M, Ortega J: Treatment of children with dysgerminoma of the ovary. Cancer 49:2608-2611, 1982 24. Brodeur G, Howarth C, Pratt C, et al: Malignant germ cell tumors in 57 children and adolescents. Cancer 48:2608-2611, 1982 25. Flamant F, Schwartz L, Delons E, et al: Nonseminomatous malignant germ cell tumors in children. Cancer 54:1687-1691, 1984 26. Hawkins EP, Finegold MJ, Hawkins HK, et al: Nongerminomatous malignant germ cell tumors in children: A review of 89 cases from the Pediatric Oncology Group, 1971-84. Cancer 58:2579-2584, 1986

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Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group.

We report treatment results in 93 children entered on study from 1978 to 1984 with malignant germ cell tumors (MGCTs), excluding dysgerminoma and tumo...
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