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Treatment of Children and Adolescents With Stage II Testicular and Stages I and II Ovarian Malignant Germ Cell Tumors: A Pediatric Intergroup Study—Pediatric Oncology Group 9048 and Children's Cancer Group 8891

From the British Columbia Children's Hospital, Vancouver, British Columbia, Canada; Emory University-Children's Healthcare of Atlanta, Atlanta, GA; Presbyterian-St Luke's Medical Center, University of Colorado, and the Children's Hospital, Denver, CO; Stanford University Medical Center, Stanford, CA; Indiana University Medical Center and James Whitcomb Riley Hospital for Children, Indianapolis, IN; The Children's Oncology Group Statistics Department, The University of Florida, Gainesville, FL; and Wayne State University School of Medicine and Children's Hospital of Michigan, Detroit, MI

Address reprint requests to Thomas A. Olson, MD, Division of Pediatric Hematology/Oncology, Ste 100, 2040 Ridgewood Dr, NE, Atlanta, GA 30322; e-mail: tolso01{at}emory.edu; CC: dcorreia{at}childrensoncologygroup.org

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To determine whether children with localized gonadal malignant germ cell tumors (MGCT) stage II testicular and stages I and II ovarian treated with four cycles of standard-dose cisplatin combined with etoposide and low-dose bleomycin (PEB) have an event-free survival (EFS) of at least 85% without significant toxicity.

RESULTS: Seventy-four patients with a median age of 10.5 years (range, 8.7 months to 16.7 years) were enrolled. Primary sites included: stage II testicular (n = 17), stage I ovarian (n = 41), and stage II ovarian MGCT (n = 16). Treatment with standard PEB resulted in 6-year EFS of 95% and overall survival (OS) of 95.7%. EFS and OS by primary site were as follows: stage II testicular, 100% and 100%; stage I ovarian, 95.1% and 95.1%; and stage II ovarian, 87.5% and 93.8%, respectively. Two patients died from recurrent disease, and one patient died of secondary acute myelocytic leukemia. Infrequent grade 3 to 4 hematologic toxicity was reported. No grade 3 to 4 renal, pulmonary, or ototoxicity was observed.

CONCLUSION: Combination chemotherapy with PEB results in excellent EFS and OS with minimal toxicity in children and adolescents with localized gonadal MGCT.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Malignant germ cell tumors (MGCT) account for 3% to 4% of childhood malignancies (< 15 years of age). Before the advent of multimodal therapy, children with MGCT could expect poor outcomes.^1–3 Subsequent therapy was based on the larger adult experience with epithelial ovarian cancer because there was a paucity of clinical trials in pediatric patients. Cyclophosphamide-based therapy improved the outcome for patients with localized MGCT,^4,5 but for patients with advanced disease, outcome remained poor. The Einhorn regimen dramatically improved the outcome of adults with testicular MGCT^6–12 and quickly became the standard of care for adults with testicular tumors. Concerns about the potential toxicity of cisplatin and bleomycin limited use of this combination in pediatric patients.^13–16 Most pediatric studies incorporated these agents in combination with cyclophosphamide-based therapy.^17,18 An excellent 2-year disease-free survival rate was reported for 13 children treated with cisplatin-based therapy.¹⁹

Pediatric MGCTs differ from their adult counterparts in histology, primary site, and age distribution.^16,18,20,21 The Pediatric Oncology Group (POG) and Children's Cancer Group (CCG) designed the prospective study (POG 9048/CCG 8891) described in this article to determine the efficacy and toxicity of combination therapy with standard-dose cisplatin combined with etoposide and low-dose bleomycin (PEB) in children with localized gonadal MGCT. Patients with stages I and II ovarian and stage II testicular MGCT were eligible for enrollment and were treated with surgical resection followed by PEB. Children with immature teratoma and stage I testicular MGCT were treated with surgery and observation and are not included in this report.^22,23 The primary objective was to ascertain whether resection and PEB therapy would result in an event-free survival (EFS) in excess of 85% for low-stage gonadal MGCT in children and adolescents.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Eligibility Criteria
Written informed consent was obtained from all patients or their guardians under the guidelines of individual institutional review boards. The pediatric POG/CCG intergroup, localized, malignant, extracranial, gonadal germ cell tumor study was open to patient registration from May 1990 to July 1995. Eligible patients included males aged 10 years or younger with stage II testicular MGCT or recurrent stage II testicular MGCT after surgical resection of a stage I tumor (Table 1). Additional eligible patients included females aged 21 years or younger with stage I or II ovarian MGCT. Histology was confirmed by central pathology review. Other eligibility criteria included no prior therapy other than surgical resection. Patients aged 11 years and older with testicular MGCT were excluded. Patients with pure immature teratomas without malignant elements were reported previously.²² Patients with pure ovarian germinoma were not included in this study.

The goals of initial surgery for patients with ovarian tumors were to resect the tumor when feasible while sparing uninvolved reproductive organs and to evaluate the extent of disease. Ascitic fluid in the peritoneal cavity (if present) was collected for cytologic examination. In the absence of ascites, peritoneal washings for cytology were obtained. Pelvic viscera, pelvic and retroperitoneal lymph nodes, omentum, peritoneal surfaces, liver surface, and subphrenic spaces were inspected. Peritoneal nodules were biopsied or resected when possible. If one ovary was involved, the tumor was removed by unilateral oophorectomy. Bilateral oophorectomy with preservation of uterus and fallopian tubes was recommended for bilateral ovarian involvement. Surgical guidelines included bimanual examination of normal-appearing contralateral ovary; complete omentectomy; and lymph node sampling of internal iliac, common iliac, low para-aortic, and perirenal chains.

Pretreatment Evaluation
Standard requirements at study entry were a medical history, physical examination (with documentation of congenital anomalies), CBC with differential, absolute neutrophil count (ANC) more than 750/µL, platelet count more than 100,000/µL, urinalysis, tumor markers (alpha-fetoprotein, beta-human chorionic gonadotropin, and lactate dehydrogenase), electrolytes, normal creatinine for age, bilirubin less than 1.5 mg/dL, ALT, alkaline phosphatase, total protein, albumin, phosphorus, magnesium, calcium, radionuclide glomerular filtration rate, and creatinine clearance within normal limits for age. Pulmonary function studies with diffusing capacity, if age permitted, or cutaneous oxygen saturation and an audiogram or brainstem auditory evoked response were required. Diagnostic imaging evaluation included chest x-ray and chest, abdomen, and pelvis computed tomography and magnetic resonance imaging and bone scan.

Histology
All eligible patients had pathologically confirmed primary germ cell tumor of the testes or ovary. Histologic subtypes included yolk sac (endodermal sinus) tumor, embryonal carcinoma, choriocarcinoma, and immature or mature teratoma with malignant elements. Ineligible histologic subtypes included pure seminoma, dysgerminoma, or teratoma without malignant elements. All histology was reviewed by the designated study pathologist.

Chemotherapy
All patients had an initial surgical resection of their testicular or ovarian tumors. Patients were required to begin chemotherapy within 21 days of their most recent surgical procedure. Chemotherapy included bleomycin 15 U/m² intravenous (IV) on day 1, etoposide 100 mg/m²/d IV on days 1 to 5, and cisplatin 20 mg/m²/d IV on days 1 to 5. Bleomycin was administered over 20 minutes. Treatment was repeated at 21-day intervals for a total of four cycles. Chemotherapy doses for infants younger than 12 months were calculated by weight as follows: bleomycin 0.5 mg/kg/dose, etoposide 3 mg/kg/dose, and cisplatin 0.7 mg/kg/dose, all administered on the same schedule.

Vigorous pre- and postchemotherapy hydration with mannitol and continuous oral magnesium supplementation were also recommended. Granulocyte colony-stimulating factor was used at the treating physician's discretion.

Toxicity
Renal toxicity was monitored by measurement of blood urea nitrogen and creatinine before each chemotherapy course and at completion of maintenance. Glomerular filtration rate or creatinine clearance was required before therapy and after four cycles. If abnormal, these studies were repeated at 12, 24, and 36 months. Pulmonary function (if age permitted) or pulse oximetry and audiograms (or brainstem evoked responses) were monitored before treatment and after four cycles. Submission of audiograms was suggested but not required. All toxicity results were graded (grades 1 to 4) according to National Cancer Institute guidelines by the treating institution. Graded toxicity scores were reported to the statistical center.

Week 12 Assessment
Physical examination and tumor marker measurements were performed with each cycle. Patients were evaluated with diagnostic imaging and serum tumor markers after four cycles of chemotherapy. Response was determined by the treating institution. Patients with normal serum tumor markers and resolution of all imaging abnormalities were considered to have achieved a complete response (CR) and received no further chemotherapy. Patients with negative imaging but persistent elevation of tumor markers were considered as having a partial response (PR). If a patient had residual imaging abnormalities at either the primary tumor or regional sites and/or declining markers, they were considered as having a PR and underwent surgical exploration. Postsurgical treatment depended on histologic findings. If the resected specimen showed no malignant disease (only mature or immature teratoma), patients were considered to have a pathologic CR and received no further therapy. Patients with malignant residual disease in the resected specimen were considered as having a pathologic PR and received two additional PEB cycles. After four cycles, patients with persistent marker elevation were considered as having no response. Patients with a more than 25% increase in size of tumor, new lesions, or increasing tumor markers were classified as having progressive disease (PD). Patients with no response and PD would be declared treatment failures and taken off study.

Follow-Up Studies
Scans (computed tomography or magnetic resonance imaging) and chest x-rays were performed 3, 6, 9, 12, and 24 months after completion of therapy. Markers, if initially elevated, were measured monthly for the first year and every 2 months during the second year.

Study Design and Statistical Analysis
Outcome analyses included EFS, which was defined as the time from study entry until disease progression, relapse, second malignancy, death, or last reported contact if none of these events occurred. Patient overall survival (OS) was defined as the time from study entry until death or the last reported contact if the patient did not die. Survival estimates were obtained using the Kaplan-Meier method.²⁴ SEs for survival rates were determined according to the methods of Peto.²⁵ The following stopping rule was used to monitor for excessive early failures. If five or more of the first 14 assessable patients experienced recurrence or died within 2 years of the start of treatment, the trial would be stopped. Enough patients were to be accrued to have sufficient power to detect a 2-year EFS more than 85%, with 90% of patients being assessable.

	RESULTS

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Between May 1990 and July 1995, 74 patients were enrolled and treated with PEB (Table 2). The early stopping rule was not met, and the study ran to completion. Seventy-three patients required only four cycles of chemotherapy. The overall 6-year EFS was 94.5%, and the 6-year OS was 95.7% (Fig 1). No patient with stage II testicular MGCT had an adverse event (EFS and OS of 100%). After the week 12 assessment, two patients had second-look surgery for imaging abnormalities. One had glial implants and received two additional cycles of PEB (incorrectly). The second patient had implants containing yolk sac elements. The latter patient was classified as having a clinical PR at week 12, but pathologically, the patient was classified as having PD. There were four events in patients with ovarian primary tumors. The patient with clinical PR, died 9 months after starting therapy. A second patient achieved CR but relapsed at 6 months and died at 46 months. Two patients developed secondary malignancies, and one died. The 6-year EFS and OS were 92.9% and 94.4%, respectively, in the patients with stage I or II ovarian tumors.

View larger version (12K): [in this window] [in a new window]   Fig 1. Event-free survival (EFS) and overall survival (OS) curves for 74 children with stage II testicular and stages I and II ovarian malignant germ cell tumors.

Eleven patients had an initial scrotal approach with biopsy (n = 2), orchiectomy (n = 6), and orchiopexy (n = 3). After the initial suboptimal approach, the procedures included inguinal approach with high ligation of the spermatic cord (n = 1), secondary high ligation of the spermatic cord after initial simple orchiectomy (n = 2), and high ligation of the spermatic cord after initial simple orchiectomy (n = 4). Eight patients had a hemiscrotectomy. These eleven patients were classified as stage II because of the initial scrotal procedure. If the initial surgery had been an inguinal orchiectomy, these patients would not have been upstaged and treated with chemotherapy. Frequently, the reason for a scrotal procedure was an error in preoperative diagnosis (torsion, hydrocele, or acute scrotum), although three patients had a mass as the preoperative diagnosis. In addition, although the protocol called for a hemiscrotectomy in cases of scrotal violation, this was only performed in eight of 11 patients. Nonetheless, all patients are surviving free of disease.

Surgery of Stages I and II Ovarian MGCT
There were 41 stage I and 16 stage II patients with primary ovarian tumors entered onto the study (Table 3). Operative notes and pathology reports were available for review in 56 of 57 patients. Evidence of preoperative microscopic tumor rupture was present in nine patients (16%). Stage II indicators were local invasion (n = 5), tumor implants (n = 3), capsule violation (n = 7), and unknown (n = 1). Surgical guidelines recommended complete, intact resection of the involved ovary with preservation of the fallopian tube if possible. Management of the primary tumor included complete oophorectomy (55 of 57 patients) and tumor enucleation and residual ovary preservation in one patient. Total abdominal hysterectomy with bilateral salpingo-oophorectomy was undertaken in one patient with a stage II tumor. The fallopian tube was removed because of concern of involvement or adherence in 14 girls. In addition, 27 patients had a normal fallopian tube removed, leaving only 15 of 56 girls with the fallopian tube preserved. Surgical guidelines were adhered to completely in only one (1.8%) of 56 patients. Deviations are listed in Table 3.

Pathology
Histologic types are listed in Table 4. The predominant malignant histology was yolk sac tumor. No pure germinomas were treated on this trial. Three patients with ovarian tumors, classified as stage II, had yolk sac elements in implants. Teratomas with malignant elements were classified according to the malignant histology and treated with chemotherapy.

	DISCUSSION

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The survival of children with MGCT has increased significantly over the last two decades. Improvements in outcome are related to the use of effective multiagent chemotherapy, including cyclophosphamide and cisplatin, and to a better understanding of tumor biology. In an earlier CCG study, the addition of cisplatin and vinblastine to vincristine, dactinomycin, cyclophosphamide, and doxorubicin as couplets every 3 weeks led to a 4-year EFS of 63% for patients with ovarian MGCT.²⁶ A preliminary pediatric trial demonstrated adequate responses and tolerable toxicity using PEB.¹⁹ However, concerns about the cumulative toxicities of these drugs in children still existed.

CCG and POG initiated the intergroup treatment protocol (POG 9048/CCSG 8891/INT-0106) described in this article for children with localized gonadal MGCT. The goal was to increase survival without significant toxicity. The study used a surgical pathologic staging system similar to other systems used in childhood malignancies (Table 1). All patients received chemotherapy according to a modified Einhorn regimen.⁸ This modification included a 67% reduction of the total bleomycin dose when compared with adult protocols because of concerns of pulmonary toxicity in young children.

The management for localized testicular tumors typically involves an inguinal orchiectomy. Several investigators have reported that the use of a scrotal orchiectomy alters lymphatic drainage, increasing the risk of lymphatic spread and treatment failure.^27,28 Therefore, in this study, patients who underwent a scrotal orchiectomy were upstaged to stage II and treated with chemotherapy. The present strategy was successful because the 6-year EFS and OS for stage II testicular MGCT treated on this protocol are both 100% (n = 17). Although the numbers are small, our future trial will allow observation for patients with a scrotal approach with clear margins.

The German Pediatric Germ Cell Group reported excellent outcome for 27 patients with low-stage testicular MGCT. Thirteen stage II and 14 patients relapsed from stage I all survived.^29–31 French Society of Pediatric Oncology (SFOP) investigators had similar results in 10 patients (five stage II patients and five patients relapsed from stage I).³² The United Kingdom Children's Cancer Study Group used a combination of carboplatin (600 mg/m²), etoposide, and bleomycin for children with MGCT.³³ As in the POG/CCG study, bleomycin was given only once during each cycle. Nineteen patients (eight stage II patients and 11 patients relapsed from stage I) had a 5-year EFS of 100%. Thus, the OS for patients with stage II testicular tumors or recurrent disease after resection for a stage I tumor treated with chemotherapy are excellent, with minimal morbidity. In contrast to the POG/CCG study, European studies included males older than 10 years. Although chemotherapy regimens and the number of administered cycles differed for all pediatric group trials, all studies share the same excellent clinical outcome.

Historically, the outcome for patients with ovarian and extragonadal tumors after surgical resection has been poor.² The introduction of effective chemotherapy has improved the outcome for these patients.^5,34–36 The present intergroup study specified that all patients with localized ovarian MGCT (stages I and II) be treated with modified PEB in a nonrandomized fashion. Patients with ovarian tumors treated in this fashion had an excellent outcome, with a 6-year EFS and OS of 92.9% and 94.4%, respectively. Although the number of patients in each study was small, recent data suggest that stage I ovarian MGCT might be successfully managed with observation.^32,37,38 A significant proportion of stage I ovarian MGCT patients had progressive disease after surgery and observation, but the results of salvage therapy have been encouraging. Five of six patients in the French Society of Pediatric Oncology,³⁹ three of three patients in the United Kingdom Children's Cancer Study Group,³³ and five of five patients in the German Pediatric Germ Cell Tumor Study Group (Maligne Keimaelltumoren 83/86/89) remain disease-free after chemotherapy for recurrent disease.⁴⁰ Therefore, a strategy of observation after surgical resection similar to what is used presently as standard treatment for patients with stage I testicular tumors may be considered for patients with stage I ovarian MGCT.

Patients with ovarian MGCT in this trial were required to have extensive surgical staging similar to what is performed in women with epithelial ovarian cancer. After reviewing operative notes, it was clear that surgical guidelines were followed strictly in only one of 56 patients. However, more than 95% of patients with stage I or II ovarian tumors were survivors after four cycles of PEB. Our data would suggest that incomplete surgical staging does not impair outcome as long as all patients receive chemotherapy. As reported at the 39th Annual Meeting of the American Society of Clinical Oncology, children with stage III ovarian MGCT had excellent 6-year EFS (96.6%).⁴¹ For future studies involving resection and observation for stage I ovarian tumors, surgical staging must be meticulous to confirm true localized disease. Of more concern was the development of secondary acute myelocytic leukemia in two patients who received a total of 2 gm/m² of etoposide. Neither of these patients had 11q23 abnormalities, and one had concomitant recurrence of MGCT. It is likely that these leukemias are related to the original MGCT, as has been reported in patients with mediastinal germ cell tumors.^42–44

In this study, limited toxicity was recorded. Significant ototoxicity has been associated with higher cumulative doses of cisplatin.^45,46 No patients developed grade 3 to 4 ototoxicity, according to grading by individual treating institutions. However, central analysis of audiograms was not required. Pulmonary toxicity secondary to bleomycin has not been well studied in pediatric MGCT studies. Pulmonary dysfunction seems to be related to cumulative bleomycin exposure and seems to be worsened with decreased kidney function.⁴⁷ Decreased pulmonary toxicity may be achieved by monitoring with pulmonary function tests, such as the diffusion of carbon monoxide, and stopping bleomycin if diffusion of carbon monoxide decreases significantly.¹⁴ In this POG/CCG study, bleomycin was given only on day 1 of each cycle to limit pulmonary toxicity. Excellent EFS was maintained despite the administration of 67% less total bleomycin than given to adult patients with testicular germ cell tumors. No major pulmonary toxicity was reported.

In conclusion, cisplatin-based combination chemotherapy improved the outcome of pediatric MGCT. This study successfully exceeded the goal of 85% long-term EFS without significant toxicity. The results further suggest that extensive surgical staging, such as retroperitoneal lymph node resection, is not necessary for patients receiving cisplatin-based chemotherapy. Most patients with testicular tumors who experience relapse after surgery and close observation can be administered successful salvage chemotherapy. The excellent survival of patients with stage II testicular MGCT led to the development of the current Children's Oncology Group trial, which includes a reduction in number of cycles and extension of the age limit to 15 years. Patients with testicular primaries, who meet strict stage I criteria after a scrotal approach, will be managed with careful observation. Patients with stage I ovarian MGCT might also be managed with careful observation, if strict surgical staging guidelines and tumor marker criteria are met. This hypothesis will be tested in next Children's Oncology Group study.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by grant Nos. U10 CA29139 from the Pediatric Oncology Group CA13539 from the Children's Cancer Group. Participating institutions and associated grant numbers are given in the Appendix.

Presented in part at the 34th Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-18, 1998, and 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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Submitted January 6, 2004; accepted June 7, 2004.

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