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Multimodal Treatment of Malignant Sacrococcygeal Germ Cell Tumors: A Prospective Analysis of 66 Patients of the German Cooperative Protocols MAKEI 83/86 and 89

From the Department of Pediatric Hematology and Oncology, Children’s Hospital, Heinrich-Heine-University, Medical Center, Düsseldorf; Department of Pediatric Hematology and Oncology, Children’s Hospital, Westfälische Wilhelms University, Medical Center, Münster; Department of Pediatric Hematology and Oncology, Prof Hess Children’s Hospital, Bremen; Children’s Hospital, Köln; Department of Pediatric Surgery, University Hospital, Mannheim; and Institute of Paidopathology, Christian-Albrecht-University, Kiel, Germany.

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

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: To evaluate a multimodal approach including surgery and cisplatinum chemotherapy for treatment of children with malignant sacrococcygeal germ cell tumors (GCT) and to compare adjuvant and neoadjuvant strategies in advanced tumors.

PATIENTS AND METHODS: Between 1983 and 1995, 71 patients with malignant sacrococcygeal GCT were prospectively enrolled onto the German protocols for nontesticular GCT Maligne Keimzelltumoren 83/86 and 89. Five patients who received no chemotherapy (n = 2) or nonplatinum chemotherapy (n = 2) or who did not undergo tumor resection (n = 1) were excluded from this analysis. Among the 66 patients analyzed were 14 boys and 52 girls. The median age was 17.4 months (range, 7 months to 119 months). Median follow-up was 79 months (range, 4 months to 145 months).

RESULTS: Fifty-two patients presented with locally advanced stage T2 tumors, and 30 patients had distant metastases at diagnosis. Patients received a median of eight cycles (range, four to nine cycles) of cisplatinum-based chemotherapy. Thirty-five patients underwent tumor resection at diagnosis and received adjuvant cisplatinum-based chemotherapy (group A). Thirty-one patients received up-front chemotherapy followed by delayed tumor resection (group B). Group B included more metastatic tumors than group A (group B, 19 of 31 patients; group A, 11 of 35 patients, P = .01). Preoperative chemotherapy facilitated complete tumor resections (group B, 20 of 31 patients; group A, five of 35 patients, P < .001) and avoided second-look surgery. Metastases at diagnosis and completeness of the first attempt of tumor resection were significant prognostic predictors; however, metastases were not predictive for patients treated with up-front chemotherapy. At 5 years follow-up, event-free survival was 0.76 ± 0.05 (50 of 66 patients), and overall survival was 0.81 ± 0.05 (54 of 66 patients). Four patients died as a result of therapy-related complications, and eight patients died of their tumors. Patients with locally advanced and metastatic tumors (T2b M1) fared better with neoadjuvant treatment [overall survival: 0.83 ± 0.09 (16 of 19 patients) versus 0.45 ± 0.15 (five of 11 patients), P = .01].

CONCLUSION: Even locally advanced and metastatic sacrococcygeal GCT can be successfully treated with up-front cisplatinum-based chemotherapy followed by delayed but complete tumor resection.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The sacrococcygeal region represents the most common primary site of benign and malignant germ cell tumors (GCT) in newborns, infants, and young children.¹ Mature and immature teratomas predominate in the first months of life, whereas yolk sac tumors (YST, synonym, endodermal sinus tumors) represent the most prevalent histologic differentiation in infants and toddlers. In most studies of both benign and malignant GCT, the sacrococcygeal site has been reported to be an adverse prognostic factor.^2-5 In sacrococcygeal teratomas, the higher relapse rate was associated with a higher rate of incomplete tumor resections.⁵ Two studies of the French and British working groups, which included malignant GCT of different primary sites treated with carboplatinum-based protocols, underlined the relevance of clinical prognostic parameters such as local stage, metastasis, and particularly alpha-fetoprotein (AFP).⁴ A recent analysis of prognostic factors in malignant sacrococcygeal GCT conducted by our study group revealed that these parameters are not prognostically relevant under intensive cisplatinum-based chemotherapy regimens (G. Calaminus, manuscript submitted for publication). However, there is general agreement that therapy for malignant GCT should follow a cooperative multimodal approach involving both pediatric surgeons and pediatric oncologists and that surgery alone may be sufficient in only some patients with small localized tumors, particularly those arising in the gonads.^4,6

In general, there are two distinct therapeutic strategies in advanced GCT. The first strategy involves application of adjuvant chemotherapy after primary resection at diagnosis, and the second strategy involves up-front chemotherapy followed by a delayed tumor resection and additional adjuvant chemotherapy. Until now, these two distinct therapeutic options have not been evaluated. Therefore, we analyzed 66 patients with regard to the therapeutic impact of both chemotherapy and surgery and the ensuing consequences for an optimized multimodal therapeutic strategy for malignant sacrococcygeal GCTs.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Between 1983 and 1995, 71 patients with malignant sacrococcygeal GCT were prospectively enrolled onto the German protocols for children with nontesticular GCTs [Maligne Keimzelltumoren (MAKEI) 83/86 and 89] of the German Society of Pediatric Oncology and Hematology. Five patients who received no chemotherapy (n = 2) or nonplatinum chemotherapy (n = 2), or who did not undergo tumor resection (n = 1) were excluded from this analysis. Five additional patients with sacrococcygeal teratoma who were reported to the MAKEI trial retrospectively only after malignant relapse were also not included in this study because they first presented with teratoma and because the surgical options after recurrence were compromised as a result of the previous surgery.

Among the 66 patients included in this study, there were 14 boys and 52 girls. The median age was 17.4 months (7 months to 119 months). The median follow-up period at the time of this report was 79 months (4 months to 145 months).

Informed consent in central data registration and statistical evaluation was obtained. The MAKEI protocols have been approved by the Ethics Committee of the Heinrich-Heine-University Düsseldorf, Germany.

Clinical Investigations
In all patients, the initial diagnostic procedures included computerized tomography (CT) or magnetic nuclear resonance tomography (MRI) and measurement of the tumor marker AFP. AFP was measured at diagnosis, during therapy (weekly until normalization), monthly for 1 year, and in increasing intervals thereafter. All patients were monitored closely for auditory and renal functions. In older children who were treated with bleomycin and who were able to cooperate, monitoring of the pulmonary function (vital capacity, forced expiratory volume) was recommended during therapy and follow-up. From 1989 on, data regarding acute treatment-related toxicity were collected. Status and late effects of both surgical and chemotherapeutic treatment were asked for in 6-monthly follow-up questionnaires.

Histopathology and Staging System
The histopathologic specimens were reevaluated by a central pathology board (head: Professor D. Harms, Institute of Pediatric Pathology, University of Kiel, Germany). The tumors were histologically classified according to the World Health Organization (WHO)–classification.⁷ In mixed tumors, the grade of immaturity of the teratoma component was determined as described by Gonzalez-Crussi et al.⁸ Patients with predominant teratoma, only microscopic foci of YST, and normal age-related AFP levels were not included in this analysis.⁹ Prechemotherapy specimens were available from 57 patients (resection, 35; biopsy, 22).

The surgical records were evaluated centrally. Tumor resection was considered complete if the tumor including the tumor pseudocapsule and the whole coccyx bone were resected in toto and without evidence of rupture of the pseudocapsule. In all patients, a complete en-bloc resection of the coccyx was strongly recommended. Microscopically, the resection margins had to be free of tumor cells (microscopically complete resection). The resection was considered microscopically incomplete if there were malignant cells at the resection margins, if the tumor was removed in more than one piece, or if a tumor cyst had been punctuated or ruptured during surgery. In case of visible tumor residues after surgery, the resection was considered macroscopically incomplete.

The tumor-node–metastasis classification of soft tissue tumors in children was applied^10,11: Tumors confined to the coccyx and the surrounding soft tissue were regarded as stage T1 tumors. If infiltration of contiguous organs (eg, sacral bone, rectum) or malignant ascites occurred, a stage T2 tumor was diagnosed. Tumors larger than 5 cm in diameter were classified as stage T1b or T2b respectively, while smaller tumors were regarded as stage T1a or T2a tumors. Lymph node metastasis (N1) was evaluated clinically with abdominal ultrasound, CT, or MRI, and during surgery, suspicious lymph nodes were sampled for histology. As a result of the lower sensitivity of the radiographic techniques compared with histologic evaluation, the proportion of tumors with lymph node metastases may be underestimated in patients who did not undergo initial surgery. Distant metastases (M1) were assessed radiographically with chest x-ray and abdominal ultrasound. Skeletal scintigraphy was not routinely recommended.

Treatment
Patients were treated with a multimodal approach that included tumor resection and cisplatinum-based chemotherapy. The doses of the chemotherapeutic agents and the applied regimens are shown in Table 1. In summary, a cisplatinum-based three-agent regimen was applied in 3-week intervals. The combinations of the chemotherapeutic agents varied between the different treatment protocols, but the doses and the mode of application remained unchanged throughout the study period. In MAKEI 89, children < 1 year old did not receive bleomycin, and children < 2 years old received only one half of the standard bleomycin dose.

Because this was not a randomized trial, the decision to treat the patients with up-front chemotherapy was mainly based on the evaluation of the surgical options. As a result, mostly patients in whom radiology showed bulky and infiltrating tumors and in whom a complete resection was considered impossible without major morbidity were chosen for delayed resection. Sixteen of 37 patients in MAKEI 83/86 and 15 of 29 patients in MAKEI 89 were treated according to this strategy.

The decision whether to perform an initial tumor biopsy was made with regard to the initial age-related tumor markers. Twenty-two patients (MAKEI 83/86: 12 patients, MAKEI 89: 10 patients) underwent tumor biopsy before neoadjuvant chemotherapy. Nine patients (MAKEI 83/86: 4 patients, MAKEI 89: 5 patients) were diagnosed clinically on the basis of radiology and tumor markers, and histology was obtained after preoperative chemotherapy. These nine patients were 12 months to 27 months old and had AFP levels between 1,304 µg/mL and 410,000 µg/mL. Therefore, a misinterpretation of the AFP levels is extremely unlikely.^9,12

In MAKEI 83/86, eight cycles of cisplatinum-based chemotherapy were applied for all tumor stages. After the fourth cycle, a delayed tumor resection or second-look resection (in case of incomplete resection on initial surgery) was recommended. MAKEI 89 proposed a maximum of six cycles of chemotherapy. Radiotherapy was not applied.

Statistical Analysis
Statistical analysis was performed using an individualized database (provided by the Institute of Medical Statistics and Documentation, University of Mainz, Germany) and the commercially available SPSS program (release 9.0. SPSS Inc., Chicago, IL, USA). For categorical data, the two-sided Pearson ² test was applied. Numerical data were calculated with the Mann-Whitney U rank test. Overall survival (OS) and event-free survival (EFS) were estimated according to the Kaplan and Meier method, and the influence of suspected prognostic factors was analyzed with the log-rank test. EFS was defined as the time from diagnosis to the first relapse or death (death of disease or death of therapy-related complication). The other patients were censored at the time of the last reported follow-up examination. A stepwise Cox regression calculation was performed with variables entered that showed P values < 0.1 in univariate analysis. P values < 0.05 were considered significant.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Initial Presentation and Therapy
Fourteen patients presented with stage T1 tumors (T1a, four patients; T1b, 10 patients). Fifty-two patients had infiltrating tumors (T2a, four patients; T2b, 48 patients). Twelve patients had lymph node metastases (N1), and 30 patients had distant metastases (lungs, 21 patients; liver, eight patients; bones: eight patients). On histologic examination, 45 patients had pure YST and 21 patients had a GCT of mixed histology with a leading YST component, additional components of mature or immature teratoma or embryonal carcinoma, and elevated serum AFP. At diagnosis, the mean AFP levels were 61,141 µg/L [range, 18 (postsurgical) to 410,000 µg/L].

In five patients, chemotherapy could not be completed according to the protocols, and these patients received four to five cycles of chemotherapy. Of these, two patients died as a result of therapy-related complications, two patients were taken off protocol after tumor progression, and in one patient, the sixth cycle was withheld because of severe complications during the previous therapy and a good tumor response. Twenty-two patients received six to seven cycles, and 39 patients received eight or more cycles of chemotherapy in accordance with the respective protocols.

Outcome: Prognostic Variables
At 5 years follow-up, the EFS of all patients was 0.76 ± 0.05 (50 of 66 patients), relapse-free survival (RFS) was 0.81 ± 0.05 (54 of 66 patients), and the OS was 0.81 ± 0.05 (54 of 66) ( Fig 1). Seven patients developed a local relapse, one patient had a distant recurrence, and four patients had a combined local and distant recurrence. Four patients died as a result of treatment-related complications (pneumonia, sepsis, intracranial hemorrhage, bleomycin-associated pulmonary fibrosis), and eight patients died of tumor progression. Outcome was comparable for both protocols (5-year EFS: MAKEI 83/86, 0.78 ± 0.07; MAKEI 89, 0.72 ± 0.08, P = .62).

View larger version (14K): [in this window] [in a new window]   Fig 1. 66 patients with malignant sacrococcygeal GCT: Event-free survival (EFS) and overall survival (OS) at 5 years follow-up.

Prognosis With Respect to Completeness of Tumor Resection
The local therapy appeared to be an important prognostic parameter: Both EFS and OS were highest after microscopically complete primary tumor resection compared with surgery with microscopic or macroscopic residual tumor (EFS, P = .05; OS, P = .02; figure not shown). This difference was most pronounced when patients who received a second-look surgery were excluded from the analysis of the first attempt of tumor resection (P = .002, Fig 2). High cumulative doses of chemotherapy did not significantly contribute to an improvement of EFS or OS in patients who received an incomplete tumor resection. However, patients with residual tumor after first surgery seemed to benefit from second-look surgery ( Fig 3).

View larger version (16K): [in this window] [in a new window]   Fig 2. 5-year EFS correlated with completeness of tumor resection. 45 patients with malignant sacrococcygeal GCT. 21 patients with incompletely resected tumors who received second-look surgery are excluded from this analysis (P = .002, log rank test).

View larger version (23K): [in this window] [in a new window]   Fig 3. 5-year EFS of 40 patients with incompletely resected sacrococcygeal GCT. Therapeutic impact of second-look surgery (P = .07, log-rank test).

Sex ratio, age at diagnosis, and follow-up time were comparable for both groups. The tumor-node–metastasis tumor stages and histology are summarized in Table 2, which shows a significantly higher proportion of metastatic tumors in group B. Patients in group B showed higher AFP values at diagnosis than group A patients (mean, 88,523 µg/L versus 37,292 µg/L, P = .025). In both groups, the rate of therapy-related deaths was not significantly different (group A, 3 patients; group B, 1 patient). The cumulative doses of chemotherapy were comparable for both groups.

Therefore, we analyzed patients with locally advanced and metastatic tumors (stage T2b M1) separately to assess the impact of a neoadjuvant strategy in advanced tumors. This analysis revealed that patients with locally advanced and metastatic tumors significantly benefited from this strategy ( Fig 4). With up-front chemotherapy and delayed resection, a 5-year EFS of 0.79 ± 0.09 (15 of 19 patients) and a 5-year OS of 0.83 ± 0.09 (16 of 19 patients) were obtained, compared with an EFS and OS of 0.45 ± 0.15 (5 of 11 patients) for patients who received adjuvant chemotherapy after initial tumor resection (P < .05). Metastatic lesions were not resected.

View larger version (14K): [in this window] [in a new window]   Fig 4. 5-year overall survival of 30 patients with locally advanced and metastatic malignant sacrococcygeal GCT (stage T2b M1) treated with initial resection versus delayed resection (P = .01, log-rank test).

Because completeness of resection was the other prognostic parameter on univariate analysis, it was the only other parameter included in multivariate analysis. On multivariate analysis of the whole cohort, completeness of resection was also prognostically significant at the 0.05 level (EFS, P = .05; OS, P = .02). However, after stratification for therapeutic strategy, completeness of resection was only borderline significant (EFS, P = .15; OS, P = .07).

Side Effects of Therapy
During the MAKEI 83/86 trial, treatment toxicity data were not collected. During the MAKEI 89 trial, the complete toxicity data of 16 patients were reported to the study coordination center. Thus, 106 chemotherapy cycles were analyzed. The predominant side effect of chemotherapy was myelosuppression, gradually increasing with higher numbers of chemotherapy cycles. WHO grade 3 or 4 leukocytopenia with a total WBC count < 2000/µL was seen after 24 of 106 cycles, and six patients suffered from severe infections (WHO grade 3 to 4). In the MAKEI 83/86 and 89 studies combined, a total of two patients died from infection (1 pneumonia, 1 sepsis). After 14 cycles, thrombocytopenia < 50,000/µL developed (WHO grade 3 to 4). One patient died from intracranial bleeding 4 months after the end of chemotherapy. At this time, he showed signs of idiopathic thrombocytopenic purpura with isolated thrombocytopenia and a hypercellular bone marrow with increased megakaryocytic regeneration. On five of 196 treatment cycles, a grade 3 to 4 nephropathy was observed, but no patient developed a grade 4 nephropathy or needed dialysis (serum creatinine > 8 mg/dL or glomerular filtration rate < 50 mL/min/1.73m²). One of the 16 patients developed a WHO grade 3 hearing loss (subjective: hearing loss correctable with hearing aid; objective:> 40 db loss at > 2 kHz).

Because of the young age of the patients, monitoring of the pulmonary function was not possible during therapy, but it was recommended for follow-up as soon as the children were old enough to cooperate. Therefore, documentation of bleomycin-related toxicity was inconsistent. We observed one patient who died as a result of pulmonary fibrosis after four cycles of chemotherapy. Finally, documentation of surgery-related complication was inconsistent, and therefore allows no detailed evaluation with respect to the two different therapeutic strategies. Five patients in whom a dysfunction of the pelvic floor was reported recovered spontaneously. We plan to evaluate these possible side effects of therapy in more detail with a retrospective survey and during the ongoing and future MAKEI protocols.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
The sacrococcygeal region represents the most common site of GCT in infants. However, there are only limited data on large cohorts of patients who have been treated according to the same therapeutic strategy and with a defined chemotherapeutic regimen. Therefore, prognostic variables in children with malignant sacrococcygeal tumors remain ill defined.

In the preplatinum era, the prognosis even of localized coccygeal malignant GCT was poor. One study reported only two survivors among seven patients with nonmetastatic disease and no survivors among five children with metastatic tumors.¹³ Another study reported progressive or recurrent tumors in eight of nine extragonadal YST when noncisplatinum regimens were applied.³ Platinum-based chemotherapy resulted in a significant improvement in the prognosis in both localized and metastatic tumors.^2-4,6,14-16 However, patients with sacrococcygeal GCT remain at higher risk of recurrence compared with their gonadal counterparts.^2,4

The following paragraphs summarize the largest series of sacrococcygeal GCT:

The data of the U.S. Children’s Cancer Study Group involving 93 patients with malignant GCT, among which there were 37 coccygeal GCT, clearly demonstrate the prognostic relevance of the completeness of tumor resection.² Thirty-one of 45 patients with nongonadal GCT and macroscopic residues after surgery relapsed. The authors concluded that the observed high relapse rate in coccygeal tumors (23 of 37 patients) was mainly because of the higher proportion of incomplete tumor resections. According to the study design, patients underwent tumor resection at diagnosis.

A recent report of the French GCT study group on patients with localized malignant GCT included 21 patients with nonseminomatous sacrococcygeal tumors.⁴ Compared with gonadal and retroperitoneal GCT, these patients had an inferior prognosis with a 3-year failure-free survival of 43% (nine of 21 patients) and a 3-year survival of 76% (overall survival: 16 of 21 patients). In this study, patients with metastatic tumors, children < 1 year old, and patients after complete primary tumor resection (watch-and-wait treatment) were excluded from analysis. According to this protocol, cisplatinum- (100 mg/m², TGM85 protocol) or carboplatinum- (400 mg/m², TGM90 protocol) containing chemotherapy was applied in children with nonresectable tumors, persistent AFP elevation after surgery, or incomplete tumor resection. The comparison of the two protocols revealed that a lower complete response rate was achieved with carboplatinum chemotherapy as first-line treatment, but after introduction of cisplatinum as second-line treatment, the results of both protocols were comparable, thus suggesting the superior therapeutic efficacy of cisplatinum compared with carboplatinum in the recommended doses.

The report by the British GCI and GCII studies included 59 children with malignant coccygeal GCT.¹⁴ The 5-year EFS for the GCI patients who received a nonplatinum-based chemotherapy was 54% (range, 35% to 71%). The 5-year EFS after carboplatinum-based chemotherapy (600 mg/m², CGII study) was 93% (range, 77% to 98%). In the recently published updated evaluation of the GCII protocol, EFS for 37 children with malignant sacrococcygeal tumors was 86.5% (range, 72.0% to 94.1%).⁶ One may conclude that the better outcome in comparison with the French study is at least partly related to the higher carboplatinum dose.

Both working groups report that in children > 1 year old, AFP levels > 10,000 µg/mL portend a poor prognosis. Our data do not support the prognostic value of AFP in children with malignant sacrococcygeal GCT. This difference may be because of the circumstance that in the other studies, gonadal GCT were also included in the analysis. However, it is more likely that differences in the therapeutic approach may account for the different results. In the British GCII protocol, 35 of 184 analyzed patients were treated with up-front chemotherapy (after biopsy: 32 patients, after clinical diagnosis: three patients). Ten additional patients underwent second-look surgery after completion of chemotherapy.⁶ In the French report, 26 of 81 patients were diagnosed clinically and received preoperative chemotherapy.⁴ One may assume that the higher proportion of patients treated with a neoadjuvant strategy in our study may account for the different clinical impact of AFP. However, as AFP was not predictive in patients treated according to an adjuvant strategy either additional factors such as the specific chemotherapeutic regimens and the use of second-look surgery should also be considered.

Our data provide important additional information because for the first time they reveal the advantages of primary chemotherapy followed by delayed tumor resection in patients with locally advanced or metastatic disease (Fig 4). This approach allowed better tumor control despite less surgical intervention. Although surgical complications were not reported consistently, one may assume that delayed surgery also bears a lower risk because the tumors are usually smaller and better circumscribed. As a result, we achieved high cure rates even in those patients with locally advanced and metastatic tumors who have previously been considered poor risk patients by other study groups.^2-4,15 Furthermore, the analysis of prognostic parameters with respect to the therapeutic strategies shows that a neoadjuvant strategy may outweigh the prognostic impact of parameters such as distant metastasis and high AFP, which may well be relevant in different therapeutic settings.

Finally, our data show that incomplete surgery should be avoided, because this appears to be an important predictor of adverse events (Fig 2). Those patients who receive incomplete first surgery may benefit from second-look surgery (Fig 3), and by the same logic, one may argue that patients with tumor residues after second-look surgery should be considered for third-look surgery. However, second-look surgery does not completely overcome the dismal prognostic impact of incomplete first surgery.

Diagnostic and Therapeutic Strategy in Sacrococcygeal Germ Cell Tumors
Age-related differences in GCT biology should be considered in the diagnostic evaluation of children with sacrococcygeal tumors. In young infants, sacrococcygeal teratomas are more frequent than malignant GCT,¹ and, therefore, in patients with age-related normal tumor markers, an initial tumor resection is indicated.⁹ Nevertheless, the same standards of complete surgery including in toto resection of the whole coccyx bone must be applied, as incompletely resected coccygeal teratomas bear a significant risk of recurrence, showing either teratoma or malignant histology^5,17

In most patients with malignant coccygeal GCT, the diagnosis can be based on radiographic findings and the AFP tumor marker. In addition, the radiographic examination will help to weigh the surgical options. In our experience, MRI (including sagittal sections) represents the gold standard because it allows evaluation for possible intraspinal spread of the tumor, which has an important impact on surgical strategy. Additional attention should be paid to infiltration of the rectal wall.

As complete resection at diagnosis was achieved only in five patients, we propose that initial resection is appropriate only for those patients with small malignant GCT in whom the MRI reveals no signs of infiltrative growth. For all other patients—and this group represents the vast majority of patients—an evaluation based on clinical and radiographic examination, tumor markers, and biopsy (when indicated) should be performed, followed by a primary chemotherapy and delayed resection. We propose that biopsy should be considered only in infants < one year old with equivocal AFP levels within or close to the age-related normal range. In older patients with significantly elevated tumor markers, an initial biopsy will not substantially contribute to the diagnosis, although may certainly be valuable for biologic studies.

In conclusion, a substantial proportion of children with malignant sacrococcygeal GCT present with locally advanced and metastatic disease. The majority of these patients can be successfully treated with neoadjuvant cisplatinum-based chemotherapy followed by delayed tumor resection. In general, the prognosis of malignant sacrococcygeal GCT is comparable to GCT at other extracranial and nontesticular tumor sites. In addition, the previously reported prognostic factors such as stage and AFP level at diagnosis seem to be modulated by the described therapeutic strategy. The completeness of the tumor resection can now be considered as an important prognostic variable. Future studies are indicated to further evaluate clinical risk factors for treatment stratification and to define standards for surgical therapy in patients with sacrococcygeal GCTs.

	ACKNOWLEDGMENTS

 
This work was supported by the Deutsche Krebshilfe e.V.

The authors thank all 120 medical centers that contributed their patients to the MAKEI studies. The authors gratefully acknowledge Susanne Dippert and Carmen Teske for expert data management and Carmen Grüttner for secretarial assistance. Finally, the authors thank Dr. M. Fritsch for his valuable contributions to this manuscript.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
1. Göbel U, Schneider DT, Calaminus G, et al: Germ-cell tumors in childhood and adolescence. Ann Oncol 11: 263-271, 2000[Abstract/Free Full Text]

2. Ablin AR, Krailo MD, Ramsay NK, et al: Results of treatment of malignant germ cell tumors in 93 children: A report from the Children’s Cancer Study Group. J Clin Oncol 9: 1782-1792, 1991[Abstract]

3. Marina N, Fontanesi J, Kun L, et al: Treatment of childhood germ cell tumors: Review of the St. Jude experience from 1979 to 1988. Cancer 70:2568-2575, 1992

4. Baranzelli MC, Kramar A, Bouffet E, et al: Prognostic factors in children with localized malignant nonseminomatous germ cell tumors. J Clin Oncol 17: 1212-1219, 1999[Abstract/Free Full Text]

5. Göbel U, Calaminus G, Engert J, et al: Teratomas in infancy and childhood. Med Pediatr Oncol 31: 8-15, 1998[Medline]

6. Mann JR, Raafat F, Robinson K, et al: The United Kingdom Children’s Cancer Study Group’s Second Germ Cell Tumor Study: Carboplatin, etoposide, and bleomycin are effective treatment for children with malignant extracranial germ cell tumors with acceptable toxicity. J Clin Oncol 18: 3809-3818, 2000[Abstract/Free Full Text]

7. Mostofi FK, Sobin LH: Histopathological Typing of Testis Tumors. Geneva, Switzerland: World Health Organization, 1993

8. Gonzalez-Crussi F, Winkler RF, Mirkin DL: Sacrococcygeal teratomas in infants and children: relationship of histology and prognosis in 40 cases. Arch Pathol Lab Med 102: 420-425, 1978[Medline]

9. Blohm ME, Vesterling-Hörner D, Calaminus G, et al: Alpha 1-fetoprotein (AFP) reference values in infants up to 2 years of age. Pediatr Hematol Oncol 15: 135-142, 1998[Medline]

10. Russell WO, Cohen J, Enzinger F, et al: A clinical and pathological staging system for soft tissue sarcomas. Cancer 40: 1562-1570, 1977[Medline]

11. UICC TNM Atlas. Illustrated guide to the TNM/pTNM classification of malignant tumours (ed 3). New York, NY: Springer, 1992

12. Schneider DT, Calaminus G, Göbel U: Diagnostic value of alpha₁-fetoprotein and human chorionic gonadotropic hormone in infancy and childhood. Pediatr Hematol Oncol 18: 11-26, 2001[Medline]

13. Brodeur GM, Howarth CB, Pratt CB, et al: Malignant germ cell tumors in 57 children and adolescents. Cancer 48: 1890-1898, 1981[Medline]

14. Mann JR, Raafat F, Robinson K, et al: UKCCSG’s germ cell tumour (GCT) studies: Improving outcome for children with malignant extracranial non-gonadal tumours—Carboplatin, etoposide, and bleomycin are effective and less toxic than previous regimens. United Kingdom Children’s Cancer Study Group. Med Pediatr Oncol 30: 217-227, 1998[Medline]

15. Kapoor G, Advani SH, Nair CN, et al: Pediatric germ cell tumor: An experience with BEP. J Pediatr Hematol Oncol 17: 318-324, 1995[Medline]

16. Göbel U, Calaminus G, Teske C, et al: BEP/VIP in children and adolescents with malignant non-testicular germ cell tumors: A comparison of the results of treatment of therapy studies MAKEI 83/86 and 89P/89. Klin Pädiatr 205: 231-240, 1993[Medline]

17. Rescorla F: Pediatric germ cell tumors. Semin Surg Oncol 16: 144-158, 1999[Medline]

Submitted September 26, 2000; accepted December 27, 2000.

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