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Prognostic Value of Tumor Size, Metastases, Extension into Bone, and Increased Tumor Marker in Children With Malignant Sacrococcygeal Germ Cell Tumors: A Prospective Evaluation of 71 Patients Treated in the German Cooperative Protocols Maligne Keimzelltumoren (MAKEI) 83/86 and MAKEI 89

G. Calaminus, D.T. Schneider, J.P.M. Bökkerink, H. Gadner, D. Harms, R. Willers, U. Göbel

From the Departments of Pediatric Hematology and Statistics and Oncology Children’s Hospital, University of Düsseldorf, Düsseldorf, and Institute for Pediatric Pathology, University of Kiel, Kiel, Germany; Department of Pediatric Hematology and Oncology, Children’s Hospital, Nijmegen, the Netherlands; and Department of Pediatric Hematology and Oncology, St Anna Children’s Hospital, Vienna, Austria.

Address reprint requests to Gabriele Calaminus, MD, Heinrich Heine University, Medical Center, Department of Pediatric Hematology and Oncology, Moorenstr 5, 40225 Düsseldorf, Germany; email: makei{at}med.uni-duesseldorf.de.

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Purpose: To evaluate the prognostic value of metastases, extension into bone, and alpha-fetoprotein (AFP) elevation in children with malignant sacrococcygeal germ cell tumors (GCTs) prospectively collected in two cooperative Maligne Keimzelltumoren (MAKEI) protocols (83/86 and 89).

Patients and Methods: Between October 1983 and October 1995, 76 of 210 registered patients with sacrococcygeal primaries presented either with pure yolk sac tumor, embryonal carcinoma (EC), or yolk sac tumor and EC mixed with immature and mature teratoma elements. Stages T1 and T2 disease were diagnosed in 15 and 61 children, respectively, 41 patients had metastases, and 35 children presented with extension into bone. At diagnosis, 22 children had an AFP elevation of less than 10,000 ng/mL. Thirty-six children showed an AFP level between 10,000 and 100,000 ng/mL, and 12 patients had values of greater than 100,000 ng/mL. Five patients died of complication during treatment and were excluded from further evaluation. Seventy-one patients could be analyzed.

Results: The 5-year relapse-free survival rate (RFS, Kaplan-Meier) was 0.76 ± 0.03 (54 of 71 patients; median observation time, 54 months after diagnosis). The RFS of patients with and without metastases was different, but not significantly so (0.71 v 0.82). The outcome of patients with extension into bone (n = 31) and without this extension (n = 40) was 0.71 versus 0.80 (RFS, 5 years). Above-normal AFP level had no prognostic significance (P = .52).

Conclusion: In children with malignant sacrococcygeal GCTs treated with an intensive, short-interval, platinum-based regimen, the stage, extent of metastases, extension into bone, and AFP level had no prognostic significance.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
MALIGNANT GERM cell tumors (GCTs) have heterogenous histology, localization, and stage. They represent 3.4% of all malignancies in children. Although it became possible to dramatically reduce the risk of treatment failure of malignant GCTs after introducing cisplatin-based therapy, it is still not clear whether metastases play a role in the outcome of children with advanced-stage disease. Experience in children with solid tumors shows that the occurrence of bone metastases and/or extension into bone defines a stage IV disease and identifies patients with unfavorable prognosis.^1,2 In children with malignant GCTs, the prognostic value of bone metastases and/or extension into bone is unclear, as specific data are not available.

The sacrococcygeal region is the most common primary localization of GCTs in infants.³ The predominant malignant histology is pure endodermal sinus tumor (yolk sac tumor; YST), followed by mixed GCTs containing embryonal carcinoma (EC) or, more often, teratoma. Children with sacrococcygeal tumors are most likely to present with tumor extension into the coccyx or sacrum or, in advanced cases, the spine. Spinal involvement has been described as an adverse prognostic factor,^4,5 in addition to high elevation of alpha-fetoprotein (AFP).⁴

Our aim was to analyze the prognostic value of metastases, extension into bone, and AFP elevation at diagnosis in 71 assessable children with localized and advanced malignant sacrococcygeal GCTs prospectively collected in two cooperative Maligne Keimzelltumoren (MAKEI) protocols (MAKEI 83/86 and MAKEI 89) of the German Society of Pediatric Oncology and Hematology.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Children with malignant sacrococcygeal GCTs, either pure YST or EC or mixed mature and immature teratoma, were selected. Only untreated patients, except for teratoma-related surgery, were included. Informed consent according to institutional guidelines was obtained for all patients. Both MAKEI protocols were approved by the Ethics Committee of the Heinrich-Heine University Düsseldorf.

Clinical Investigations
In all patients, the initial diagnostic procedures included computed tomography (CT) or magnetic resonance imaging (MRI) and measurement of tumor marker (AFP) in serum. Criteria for the diagnosis of a malignant GCT with YST elements were CT or MRI revealing a sacrococcygeal tumor and AFP elevation more than 25 ng/mL in children older than 2 years of age (other reasons for AFP elevation^6,7 were excluded). For definition of AFP elevation (AFP >25 ng/mL) we used the International Consensus of the Pediatric Germ Cell Tumor Working Group for children older than 2 years of age with intracranial GCTs.⁸ Regarding the AFP levels, we adopted the definitions given in the International Germ Cell Tumor Consensus Classification (IGCCC)⁹ for adults and for children according to the data on localized malignant GCTs of the French Society of Pediatric Oncology studies.⁴

Histopathology and Staging System
All histopathologic samples were reviewed by a board of pathologists (D. Harms, Institute for Paidopathology, University of Kiel; H. Müntefering, Institute for Paidopathology, University of Mainz; Th. Löning, Institute for Pathology, University of Hamburg; and O. Wiestler Institute for Neuropathology, University of Bonn, Germany) in addition to the evaluation of the local pathologist. The tumors were histologically classified according to the World Health Organization classification for testicular and ovarian GCTs.^10,11 In mixed tumors, the grade of immaturity of the teratoma component was defined according to the grading system of Gonzalez-Crussi et al.¹² If teratoma was the predominant histology, with microscopic foci of YST only and normal age-related AFP levels, patients were excluded from analysis.

For clinical staging, the current tumor-node-metastasis classification of soft tissue tumors in children was used.¹³ If the tumor was confined to the surrounding soft tissue of the coccyx, it was regarded as a stage T1 tumor. In case of contiguous infiltration of other organs (eg, sacrum, spinal canal, bladder, rectum, or muscle) or if malignant ascites were present, a stage T2 tumor was diagnosed. Tumors greater than 5 cm in diameter were classified as stage T1b and T2b, respectively, whereas tumors less than 5 cm in diameter were regarded as stage T1a and T2a.

Regional and distant lymph node metastases (N1) as well as distant metastases in liver, lung, and other organs (M1) were documented and evaluated separately. Lymph node metastases (N1) were evaluated clinically by ultrasound, CT, or MRI and during surgery by sampling for histology. Distant metastases (M1) were assessed radiographically with chest x-ray, ultrasound, CT, or MRI.

Special features were investigated to define extension into bone as precisely as possible. Extension into bone, diagnosed by radiologic imaging and histopathology after resection, was defined as infiltration by contiguous tumor into the coccyx, sacrum, or other bone structures. A special group of patients were those with tumor growth into the spinal canal. Bone metastases were verified by bone scintigraphy or other imaging.

Treatment
Subjects were treated either under MAKEI 83/86 or MAKEI 89. In both protocols, children were treated with a multimodal approach that included surgery and a cisplatin-based three-agent regimen applied in 22-day intervals, as summarized in Table 1. In patients with bulky disease and/or metastases, without the prospect of complete tumor resection, three to four preoperative courses of chemotherapy were proposed, followed by tumor resection. In children with incomplete resection at time of first operation, the recommendation was three to four courses of chemotherapy followed by second-look surgery. Radiotherapy was not part of the applied protocols. The differences between the two protocols were the use of bleomycin and vinblastine (MAKEI 83/86) as opposed to ifosfamide and etoposide (MAKEI 89) and the decrease of the total number of courses in advanced stages from eight courses (MAKEI 83/86) to six courses (MAKEI 89).

Imaging. In case of a signal tumor at start of chemotherapy, imaging was repeated after every two courses, with the imaging showing most efficacy for control of tumor response. If the tumor was primarily resected, diagnostics were repeated after two to three treatment courses. Localizations of metastases, if diagnosed initially, were examined by imaging in the same intervals to evaluate response to therapy. A complete remission was defined as no evidence of disease or metastases on imaging and return to normal AFP level.

Careful evaluation of both the serum AFP and the tumor imaging data was mandatory. Patients who showed no decline or an increase of AFP during treatment, as well as patients with no adequate response by imaging, were removed from study, and an alternate treatment was proposed.

Follow-Up Investigations
After the end of treatment, all patients were followed for clinical and imaging end points for up to at least 5 years. For the first 2 years, follow-up was first monthly and then quarterly; thereafter, follow-up was twice a year and then yearly.

Completeness of Data Collection
Collection of data regarding surgical protocol, histologic report, and treatment data was complete in all evaluated patients. Follow-up details were requested from the registering institutions semiannually.

Statistical Analysis
The data were recorded and monitored at the Children’s Hospital, University of Düsseldorf. The database was closed after August 1, 1999, and subject data were followed until September 2001. Data were analyzed with SAS, individualized version, provided by the German Children’s Cancer Registry and Institute of Medical Statistics and Documentation, University of Mainz, Germany (J. Michaelis). The relapse-free survival (RFS) and event-free survival (EFS) were estimated according to the Kaplan-Meier method, and the influence of suspected prognostic factors was analyzed with the log-rank test. For categorical data, the two-sided Pearson ² and Fisher’s exact test were used. EFS was calculated from the date of diagnosis to the date of relapse or death (death of disease) or death of therapy-related complication. P values .05 were considered significant.

Five patients died of therapy-associated complications during treatment and were excluded from statistical evaluation of the prognostic factors.

Characteristics of the Evaluated Children With Primary Sacrococcygeal Malignancy
Between October 1983 and October 1995, 210 children with sacrococcygeal GCTs were registered in both protocols. Seventy-six patients presented with a malignant histology (YST, EC, or EC plus YST plus teratoma) and received the described three-agent cisplatin-based chemotherapy according to protocol guidelines (Table 1).

Thirty-nine patients were enrolled onto MAKEI 83/86 and 37 onto MAKEI 89 (59 girls and 17 boys). The age range was between birth and 120 months, with median ages of 18 and 15 months for MAKEI 83/86 and MAKEI 89, respectively. Three patients who had received only surgery for their primary benign sacrococcygeal tumor were evaluated at the time of malignant relapse. The observation time, which was defined as the time from the date of diagnosis until the date of the last examination of the evaluated patients, ranges between 5 and 181 months, with a median follow-up of the surviving patients of 108 months. Stage T1a was diagnosed in three children, T1b in 12, T2a in four, and T2b in 52. Nine patients had only lymph node metastases, 12 presented with lung metastases, five with liver metastases, and five with combined metastases in more than one organ. Seven children had combined metastatic sites involving bones: four with vertebrae, two with femur metastases, and one with a metastasis in the humerus (Table 2).

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The treatment results are summarized with respect to occurrence of events and survival in Table 3. The predominant histology was YST in 72 patients, of whom 49 were diagnosed with pure YST. Four children had EC as primary diagnosis.

With respect to the two consecutive studies, EFS and RFS are summarized in Table 3 and show no statistically significant differences. In MAKEI 83/86, nine relapses occurred, whereas in MAKEI 89, eight relapses occurred. Of the 17 relapses, 11 children developed a recurrence within the primary tumor area, three patients experienced relapse outside the primary tumor site, and three patients had tumor regrowth within the primary tumor area as well as distant metastases at time of recurrence. All patients with advanced disease (n = 56) received six to eight courses of chemotherapy.

As there are no differences in RFS between the two protocols, the relapse rates of all patients are evaluated together with respect to tumor stage and metastases (Fig 1) as well as extension into bone (Table 4). Patients treated under protocol guidelines with T1 tumors presented with RFS at 5 years of 0.73 ± 0.08 (11 of 15 patients), which was nearly equal to the RFS of patients with T2 tumors (0.77 ± 0.02; 43 of 56 patients). These results indicate that the local tumor stage had no influence on outcome (P = .71).

View larger version (13K): [in this window] [in a new window]   Fig 1. Relapse-free survival with respect to metastases.

The 5-year RFS for patients presenting with metastases at diagnosis was 0.82 ± 0.04 for patients without (27 of 33 patients) and 0.71 ± 0.04 for patients with (27 of 38 patients) metastases (P = .33; Fig 1). In our series, the latest recurrence occurred 24 months after diagnosis. The presence of metastases at time of diagnosis did not significantly influence the 5-year RFS of patients treated according to our protocol.

The effect of various metastatic sites at presentation on the RFS at 5 years was assessed. Five-year RFS was 0.78 ± 0.12 with lymph node involvement, 0.75 ± 0.10 for patients with lung metastases (nine of 12 patients), 0.80 ± 0.20 with liver metastases (four of five patients), and 0.40 ± 0.33 with combined metastases (two of five patients). These five patients had T2b tumors (three with lymph node and lung metastases and two with liver and lung metastases). In comparison, the RFS of children with combined metastases including bone metastases was 0.71 ± 0.17 (five of seven patients; P = .71). This difference was not statistically significant (P = .81). Patients with combined visceral metastases had the worst outcome. Bone metastases had no effect on prognosis.

In 40 children, no tumor extension into bone was seen at diagnosis. In 14 patients, the coccyx was infiltrated, 11 patients showed an additional infiltration of the sacrum, and six children had tumor growth into the spinal canal (Table 4). In patients with tumor extension into bone, nine relapses were observed. In patients without bone extension, eight suffered relapse. The 5-year RFS was 0.80 ± 0.03 and 0.71 ± 0.04 for patients with and without tumor extension into bone, respectively (P = .45). Thus, extension into bone did not seem to be statistically significant. This unexpected result is supported by the fact that relapse risk did not increase with either sacrum or spinal canal involvement.

In 66 patients, AFP was evaluated at the time of diagnosis. Fifty-one patients were older than 24 months at diagnosis (Fig 2). AFP ranges were set according to French Society of Pediatric Oncology data and the International Germ Cell Tumor Consensus Classification. In children with AFP less than 10,000 ng/mL (n = 21), seven relapses occurred (RFS, 0.67 ± 0.07); seven of 33 patients with AFP between 10,000 and 100,000 ng/mL developed a recurrence (RFS, 0.79 ± 0.04). Twelve children had AFP levels greater than 100,000 ng/mL at diagnosis; two experienced relapse (RFS, 0.83 ± 0.09; P = .52). In this particular patient group, the 5-year RFS was independent of the AFP level at the time of diagnosis. This indicates that patients with high AFP levels at diagnosis do not require a more intensive treatment than that defined by the stage of the disease.

View larger version (17K): [in this window] [in a new window]   Fig 2. Relapse-free survival with respect to initial alpha-fetoprotein values.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

In children with solid tumors, it is commonly accepted that metastases, especially bone metastases and tumor extension into bone, are prognostically relevant. In pediatric patients with malignant sacrococcygeal GCTs, these factors had up to now not been specifically evaluated. The only exceptions were the recommendation to resect the coccyx en bloc with the tumor¹⁵ and the observation in the German MAKEI series that incomplete resection of the tumor has a significant influence on prognosis.¹⁶

In the last 30 years, different chemotherapy regimens have been tested in this disease group with varying success.^14–17 Data of the United Kingdom Children’s Cancer Study Group (UKCCSG) study on malignant GCTs registered between 1979 and 1987¹⁸ described the results of several chemotherapy regimens: the common regimen of vincristine, dactinomycin, and cyclophosphamide was seen to be ineffective (EFS of 8%), whereas good results were obtained with high-dose vincristine, dactinomycin, and cyclophosphamide with or without doxorubicin, resulting in an EFS of 87%, but with unacceptable side effects. In the 1980s, new platinum-based regimens demonstrated similar efficacy (84%) and fewer side effects in children with malignant GCTs.^19,20 In the German series of 66 patients with malignant sacrococcygeal tumors, the EFS was 0.76 ± 0.05 (50 of 66 patients).¹⁶ Patients with sacrococcygeal tumors remained at higher risk of recurrence compared with those having other primary tumor sites.^21,22

Even though the sacrococcygeal region is the most frequent site of localization in children with GCTs, only limited data are available for risk factors such as stage, metastatic site, bone involvement, and level of tumor markers at time of diagnosis.²³ From recent analyses of data in pediatric malignant sacrococcygeal as well as mediastinal tumors, the prognostic effect of incomplete tumor resection has become apparent.^16,24,25 In contrast, in urogenital malignant GCTs in young girls, resection is not of prognostic value.²⁶

In adults, it is well known from the International Germ Cell Consensus Classification of 1997⁹ that lung, liver, bone, or brain metastases were adverse features, each associated with decreased 5-year survival rates of less than 50%.

Our results are similar to recent data of the UKCCSG, in which 98 patients were treated under two consecutive protocols (GCI and GCII).²⁷ In GCI, patients mostly received bleomycin, etoposide, and cisplatin (21 of 40 patients), with a cisplatin dose of 100 mg/m². In GCII, 46 patients received carboplatin, etoposide, and bleomycin, with a carboplatin dose of 600 mg/m². There was a median number of six courses in each study.

The EFS for the group that received carboplatin, etoposide, and bleomycin was significantly better than the EFS for the group receiving bleomycin, etoposide, and cisplatin (57% v 87%; P = .02). Fifty-nine children presented with malignant sacrococcygeal primaries, with a 5-year actuarial survival rate of 77% in GCI and 96% in GCII. Patients with sacrococcygeal primary tumors did not have a worse outcome compared with children with other primary sites, such as ovary or testis. The only difference described is the poorer outcome of children with stage IV disease and/or nonsacrococcygeal primary tumors.

The French Working Group examined prognostic factors for outcome in 81 children older than 1 year with localized malignant nonseminomatous GCTs, including 21 children with sacrococcygeal tumors.⁴ Patients with metastatic tumors were excluded from analysis, as were children younger than 1 year of age and patients who underwent complete resection without subsequent therapy. In these studies, cisplatin 100 mg/m² (TGM85 protocol) or carboplatin (400 mg/m², TGM90 protocol) was administered as part of a multidrug regimen to all patients with unresectable tumors, persistent AFP elevation after surgery, or incomplete tumor resection. Patients with sacrococcygeal primaries had a lower 3-year failure-free survival rate (43%; nine of 21 patients) than patients with testicular (91%; 10 of 11 patients) or retroperitoneal (60%; three of five patients) malignant tumors. The comparison of the two protocols also reveals better therapeutic efficacy of cisplatin, as most of the patients with initial treatment failures while receiving carboplatin could be treated with salvage therapy with second-line cisplatin. This observation is different from the UKCCSG experience with carboplatin, etoposide, and bleomycin. However, these observations may be the result of different dosages and synergistic effects of the drugs involved.

In the French series of patients with different primary sites, AFP levels at diagnosis were of prognostic value. Our results do not support these findings. High AFP levels at diagnosis did not indicate poor outcome. In addition, in our limited series, neither the occurrence of metastases nor bone metastases or extension of tumor into bone had a significant effect on prognosis. Only the presence of visceral metastases may influence outcome.

Patients with tumor size greater than 5 cm and visceral metastases have a poor prognosis. These patients may require the most intensive treatment. The different findings in adult series possibly reflect a different tumor biology and encourage further investigations in children. Bussey et al²⁸ studied six pure sacrococcygeal YSTs with conventional cytogenetic techniques. Schneider et al²⁹ summarized the data on comparative genomic hybridization of nine sacrococcygeal pure YSTs. Both studies report recurrent changes on chromosomes 1, 6, and 21 and the absence of the isochromosome 12p, which is pathogenomonically associated with GCTs in adults. Interestingly, the patterns of chromosomal imbalances of sacrococcygeal GCTs were similar to those of testicular GCTs in infants. This may be explained in light of recent studies that confirm the common cellular origin of gonadal and extragonadal GCTs that both arise from the primordial germ cell.³⁰

Currently, more than 70% of children with advanced malignant sacrococcygeal tumors can be cured by platinum-based intensive treatment protocols, regardless of stage.¹⁶ Two thirds of the children are diagnosed with advanced tumors, of whom 50% show additional metastases at diagnosis and extension into bone as a result of contiguous tumor growth. We have demonstrated in this study that tumor stage and metastases, extension into bone, and AFP elevation do not have a significant effect on outcome if an intensive platinum-based treatment is applied.

	ACKNOWLEDGMENTS

 
We thank Carmen Teske and Susanne Koch for expert data management, Barbara Engel and Greg Podsakoff for their expert help in language editing, and the medical centers that contributed their patients to the MAKEI studies.

	NOTES

 
Supported by the Deutsche Krebshilfe eV, Bonn, Germany; grant no. 50-2699.

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TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted March 27, 2000; accepted November 15, 2002.

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