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Prognostic Factors in Children With Localized Malignant Nonseminomatous Germ Cell Tumors

From CRLC Oscar Lambret, Lille; CRLC Val d Aurelle Paul Lamarque, Montpellier; Institut Curie, Paris; CHRU Purpan, Toulouse; CHRU Sud, Rennes; Institut Gustave-Roussy, Villejuif, France; and the Royal Marsden NHS Trust, Sutton, Surrey, United Kingdom.

Address reprint requests to Marie Christine Baranzelli, MD, Pediatric Department, Centre Oscar Lambret, 3 rue F Combemale, BP 307, 59020 Lille Cédex, France; email mc-baranzelli{at}o-lambret.fr

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PURPOSE: Prognostic factors were studied in children older than 1 year who were treated with chemotherapy for extracranial localized malignant non seminomatous germ cell tumors.

PATIENTS AND METHODS: Data from two consecutive protocols were pooled. The TGM 85 (1985-1989) protocol consisted of alternating courses of cyclophosphamide, dactinomycin and vinblastine, bleomycin, and cisplatin at a dose of 100 mg/m² per course. The TGM 90 (1990-1994) protocol was initiated with carboplatin 400 mg/m² substituted for cisplatin as the only modification to the previous protocol.

RESULTS: We examined alpha-fetoprotein (AFP) levels, disease stage, and primary site and identified three prognostic groups. Patients with a poor prognosis had either an AFP level 10,000 ng/mL or stage III disease and a sacrococcygeal or mediastinal primary site; such patients represented 46% of the patient population and experienced a 43% 3-year failure-free survival rate and a 77% overall survival rate. Patients with a good prognosis had an AFP level less than 10,000 ng/mL, stage I or II disease, and a testicular, ovarian, perineal, or retroperitoneal primary site; such patients represented 22% of the patient population and experienced no treatment failures. The other patients were classified in the intermediate prognosis group and represented 37% of the patient population, with an 81% 3-year failure-free survival rate and a 92% overall survival rate.

CONCLUSION: Initial AFP level, disease stage, and primary site are the most important prognostic factors in this analysis. Prognostic models for pediatric germ cell tumors should allow the stratification of patients for a risk-adapted approach to treatment.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
PEDIATRIC GERM CELL TUMORS (GCTs) are rare and represent approximately 3% of malignant tumors in this age group.¹ Despite different patterns of presentation, the prognosis of GCTs in childhood has improved with the introduction of protocols used for adult GCTs, which are much more common.^2-4 Earlier treatment programs that included combinations of cyclophosphamide and dactinomycin yielded poor results, especially in advanced extragonadal stages.^5,6 The addition of cisplatin produced a marked increase in cure rates in childhood GCTs up to 70% to 80%.^5,7-11 In contrast to nonseminomatous germ cell tumors (NSGCTs) in adults,^12-17 prognostic factors have been less clearly defined in children, because most series are too small and/or heterogeneous. The French Society for Pediatric Oncology (SFOP) conducted two consecutive studies (TGM 85 and TGM 90) from January 1985 to December 1994, which are the basis of this analysis. The aim of this study was to assess prognostic variables among patients with secreting GCTs. The patient population includes exclusively nonmetastatic patients with secreting NSGCTs. Patients with nonsecreting immature teratoma and patients with localized secreting tumors treated with surgery only are not included in this analysis.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
One hundred fifty-two patients between 1 and 18 years of age with newly diagnosed localized secreting malignant GCTs were enrolled onto two consecutive clinical trials of SFOP. From January 1985 to December 1989, protocol TGM 85 enrolled 65 patients; from January 1990 to December 1994, protocol TGM 90 enrolled 87 patients. Twenty patients on TGM 85 and 34 patients on TGM 90 who underwent complete surgical resection at diagnosis and who received no further treatment were not eligible for adjuvant chemotherapy. These patients were followed expectantly and were not included in the analysis, because they were considered to be low-risk patients. Because elevated physiologic alpha-fetoprotein (AFP) levels in infancy and persistently elevated physiologic AFP levels up to 1 year precluded accurate statistical analysis of AFP levels in this group, 17 children younger than 1 year of age were not included in the analysis.

Staging was performed according to clinical disease extent at presentation and postsurgical findings¹⁸ (Table 1). Tumor marker (AFP and beta–human chorionic gonadotropin [BHCG]) measurements were obtained in all patients at diagnosis before the first course of chemotherapy and before each course thereafter. In the studied population, 26 patients were treated on the basis of tumor markers without histologic confirmation, and histology at diagnosis was accordingly available in 55 cases. Thirty-seven tumors were diagnosed as yolk sac, containing at least one different component in 18 cases. In 12 tumors, the histologic proposal was embryonal carcinoma, either pure in four cases or mixed in eight specimens containing teratomatous elements. The six remaining tumors were identified as choriocarcinoma (two patients) and immature teratoma (four patients). When tissue diagnosis was available, there was no clear consistency between tumor markers and histology.

Treatment Program
Patients with unresectable disease at diagnosis, incomplete resection, or persistently elevated AFP levels after surgery received chemotherapy according to the ongoing first-line chemotherapy. Both the TGM 85 and TGM 90 regimens comprised dactinomycin, cyclophosphamide, vinblastine, and bleomycin at a similar total dose per course, but doses were given according to different schedules (Fig 1). The TGM 85 regimen was cisplatin-based, whereas the TGM 90 regimen substituted carboplatin for cisplatin.

View larger version (16K): [in this window] [in a new window]   Fig 1. TGM 85 and TGM 90 chemotherapy protocols. All symbols indicate that the drug was given on that day. Drugs: AMD, dactinomycin; CTX, cyclophosphamide; VBL, vinblastine; Bleo, bleomycin; CDDP, cisplatin; and Carbo, carboplatin.

Patients on TGM 85 received three cycles of chemotherapy. Patients on TGM 90 received two additional cycles after normalization of their AFP levels. If biologic response to chemotherapy was incomplete after two courses (persistently elevated AFP and/or BHCG levels), then second-line therapy comprising etoposide and ifosfamide, with or without cisplatin, was given.

Statistical Method
Response criteria. Both protocols were evaluated for the following response criteria: complete remission (CR) after induction chemotherapy, continuous complete remission after induction treatment, alive without disease (regardless of the number of attempts or the time to achieve remission), failure-free survival (FFS), and overall survival (OS). All survival times were calculated from treatment initiation. In the TGM 85 protocol, treatment failure was defined as death, relapse, or an incomplete remission after induction treatment. In the TGM 90 protocol, treatment failure was defined as death, relapse, or an incomplete remission after second-line treatment, because patients who did not achieve a CR after induction treatment were allocated to a second-line treatment protocol.

Statistical analysis. Response rates were compared using the Pearson ² test or Fisher's exact test when appropriate for categorical variables. Time-to-event curves were estimated by the Kaplan-Meier method at 3 years.¹⁹ Univariate survival rates were compared using the log-rank test.²⁰ Multivariate analyses for identifying independent prognostic factors were made using the Cox proportional hazards regression modeling technique for the analysis of times to events.²¹

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Analyses of survival and events were performed as of November 1997, with a median follow-up period of 90 and 56 months in the TGM 85 and TGM 90 protocols, respectively.

Patient Characteristics
Forty-one and 40 eligible patients aged 1 year or older were treated on the TGM 85 and TGM 90 protocols, respectively. The distribution of their clinical characteristics and AFP levels was not statistically different between the two protocols (Table 2).

Remission, Failures, and Survival
The CR rate was 90% in the TGM 85 protocol. Four patients failed to achieve remission. The CR rate in the TGM 90 protocol was similar, with only four failures. However, the CR rate after first-line treatment was only 58%; the 90% CR rate was achieved when responses to first- and second-line treatments were considered. Apart from four primary failures in each protocol, there were eight relapses in TGM 85 and nine relapses in TGM 90. One patient in TGM 90 developed acute nonlymphoblastic leukemia. Five TGM 85 patients died (all after relapses), and eight patients died in TGM 90 (four primary refractory cases, three relapses, and one case of acute nonlymphoblastic leukemia). At last follow-up, 36 patients (88% ± 5.1%) in the TGM 85 protocol and 31 patients (78% ± 6.6%) in the TGM 90 protocol were in CR. Among the study population of 81 patients, 26 patients (eight primary refractory cases, 17 relapses, and one case of acute nonlymphoblastic leukemia) experienced initial treatment failures. The 3-year FFS rate was 68%. Thirteen patients (five TGM 85, eight TGM 90) died, and the 3-year survival rate was 87%.

Prognostic Factors
In the univariate analysis, age younger than 10 years (P = .27), sacrococcygeal or mediastinal primary site (P = .05), and elevated AFP values (P < .001) were associated with poorer FFS. No factor significantly influenced OS. This was mainly due to the success of salvage treatments and the small number of deaths observed in this patient population (Table 3).

Multivariate Analysis
As a first approach, classical multivariate methods identified AFP level as the most important prognostic variable. AFP values greater than 10,000 ng/mL characterized a group of 35 patients with higher risk of failure and poorer outcome (19 treatment failures and nine deaths); no other factor seemed to significantly influence prognosis in this category of patients. When the AFP factor was excluded, disease stage (P = .025) and primary site (P = .008) were significantly correlated with failure. These variables were used in the category of patients with AFP levels less than 10,000 ng/mL. For these remaining 46 patients, disease stage (P = .024) and primary site (P = .025) significantly influenced risk of failure, with relative risks of 2.5 and 1.8, respectively.

To set up prognostic groups using a combination of these factors, a multivariate proportional hazards regression model was applied. Again, when main effects were used, only AFP level was statistically significant. The significance of disease stage (P = .036) and primary site (P = .019) only became apparent when interaction terms were introduced into the model. This model used all patients, three main effects (AFP level, disease stage, and primary site), and two interaction terms with AFP. Results indicate a significant association for AFP level (P < .01), primary site (P = .021), and disease stage (P = .021), as well as an AFP level interaction with disease stage (P = .027) and primary site (P = .11). The regression coefficients and the coding associated with each covariable were then used to establish a prognostic index that allowed a stratification of groups of patients according to their risk (Table 4). This index was formed by first multiplying each regression coefficient by the code corresponding to the value of the covariable and then summing the results over all covariables to obtain a prognostic index.

Patients with a prognostic index greater than 3 were classified into the poor prognosis group. This poor prognosis group consisted of patients with AFP levels 10,000 ng/mL or patients presenting with stage III disease and extragonadal or retroperitoneal primary site. Stage I or II patients with AFP levels less than 10,000 ng/mL and presenting with either gonadal nonretroperitoneal primary site were considered good prognosis patients, with a prognostic score of zero. Patients presenting with either stage III disease or extragonadal nonretroperitoneal primary site and AFP levels less than 10,000 ng/mL were classified into the intermediate prognosis group. Their prognostic scores ranged between 1 and 3.

Overall, 22%, 37%, and 46% of patients were classified into good, intermediate, and poor prognosis groups, respectively. Prognostic groups were equally distributed between the two treatment protocols, with nine, 14, and 18 patients on the TGM 85 protocol classified into good, intermediate, and poor prognosis groups, respectively, compared to nine, 12, and 19 patients on the TGM 90 protocol, respectively. Failure to achieve CR increased between prognostic groups and was 0% in the good prognosis group, 8% in the intermediate prognosis group, and 16% in the poor prognosis group. At the time of follow-up, continuous first CR was maintained for all patients in the good prognosis group, compared with 81% and 43% of patients in the intermediate and poor prognosis groups, respectively. Continuous CR rate, regardless of the number of treatments, was 100% in the good prognosis group, compared with 92% and 68% in the intermediate and poor prognosis groups, respectively. No failures or deaths were observed among patients in the good prognosis group. In the intermediate prognosis group, five of 26 patients experienced treatment failures: two patients with primary failure died within 1 year of diagnosis, and three relapsed patients are alive after salvage treatment at 58, 64, and 90 months after relapse. In the poor diagnosis group, 21 of 37 patients experienced treatment failures. Six patients had primary failure: three died and three are alive after salvage treatment, with minimum follow-up of 6 years. Fourteen patients relapsed, and seven are alive after salvage treatment at a median follow-up of 45 months after relapse (range, 7 to 79 months). One patient died from an unrelated cause at 34 months. Median time to death after relapse was 21 months (range, 6 to 34 months).

Three-year FFS and OS rates for each group are shown in Figs 2 and 3. Among patients in the good prognosis group, no failures were observed. Among patients in the intermediate prognosis group, the 3-year FFS and OS rates were 81% and 92%, respectively. Among patients in the poor prognosis group, FFS and OS rates were 43% and 77%, respectively.

View larger version (14K): [in this window] [in a new window]   Fig 2. Failure-free survival by risk group. – –, good prognosis group; – –, intermediate prognosis group; - - - , poor prognosis group.

View larger version (15K): [in this window] [in a new window]   Fig 3. Overall survival by risk group. – –, good prognosis group; – –, intermediate prognosis group; - - - , poor prognosis group.

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
Depending on patient selection and treatment modalities, survival in pediatric series of NSGCTs ranges between 75% and 95%.^6,22-25 Results of the TGM 85 and TGM 90 protocols do not differ from previous cooperative series. However, data from pediatric GCT studies are difficult to compare. Staging modalities and staging systems may vary from one report to another; patients with testicular tumors, germinomas, or teratomas are or are not included; and indications for chemotherapy may vary among groups. Although historical comparisons between consecutive protocols within a cooperative group with identical eligibility criteria can be made, large variability in allocation of patient prognostic groups or treatments has made evaluation among series impossible.

By contrast, a consensus regarding the prognostic classification of adult GCTs has been reached, allowing the comparison of results among clinical trial groups. GCTs in adulthood affect mainly young men, and testicular cancer is currently the most common malignancy in men aged 20 to 34 years. The majority of adult patients with testicular GCTs initially present with metastatic disease, and several studies have been conducted to assess prognostic variables in metastatic patients.^12-16 Some variations are observed in the results of these studies, which are likely due to the different sizes of databases.¹⁷ The largest data collection has involved participating centers from 10 countries and has provided information about several thousands of patients to achieve the International Germ Cell Consensus Classification.¹⁶ For NSGCTs, independent adverse factors that have been identified include mediastinal primary site, presence of nonpulmonary visceral metastases, and the degree of elevation of AFP, BHCG, and lactate dehydrogenase. These conclusions cannot be applied to the pediatric population, because tumors develop in different sites and with different patterns. In pediatric protocols for extracranial GCTs, children are often treated with the same regimen, regardless of their clinical characteristics. Several groups adjust the number of administered courses according to normalization of markers that may introduce a variable with prognostic implication.^25,26 Previously, only disease stage had been shown to be a prognostic factor in pediatric GCTs.^6,8,11,18 Gonadal or extragonadal sites are sometimes mentioned, but this factor is closely associated with disease stage, because more gonadal tumors are localized and treated with radical surgery. No prognostic significance has been demonstrated for initial values of AFP and/or BHCG markers⁵ or for histology.^27,28

In TGM 85 and TGM 90 protocols, treatment strategies for nonmetastatic patients were identical. In TGM 90, carboplatin was substituted for cisplatin to reduce toxicity; cisplatin was considered for patients who failed to achieve normal markers after two cycles. This change led to a significant decrease in the CR rate for first-line treatment from 90% with cisplatin in TGM 85 to 58% with carboplatin in TGM 90.²⁶ When second-line treatment was given, the overall CR rate was similar in both protocols. However, OS in TGM 90 was 78%, compared with 88% in TGM 85. This difference in efficacy observed with TGM 90 might have contributed to the identification of AFP as a prognostic factor when suboptimal treatment was given. This suggests that intensive cisplatin-based chemotherapy results in higher survival rates in patients with localized tumors, regardless of their AFP level and tumor site. Conversely, the price for such an approach is the overtreatment of a subset of patients with better prognostic features.

Data were pooled from two protocols with the same patient characteristics; this provided enough information to allow univariate and multivariate statistical evaluation to be performed. The prognostic value of the most adverse factor, AFP elevation, is emphasized by 19 failures and nine deaths among 35 patients with pretreatment AFP levels greater than 10,000 ng/mL. We did not identify BHCG as an independent prognostic factor. However, BHCG-secreting tumors accounted for a small proportion of patients, and the significance of this variable might have prognostic value in a larger pediatric database.

When using AFP levels to stratify patients, the results of our statistical analysis suggest the important prognostic features of disease extent and tumor site. Retroperitoneal and testicular primary sites are associated with a better outcome. Such results are also in agreement with previous studies in adults.¹⁶ Our study included female patients, and we found that the ovarian site was, in the statistical analysis, similar to the testicular site in boys. Disease at the sacrococcygeal site, seen only in pediatric oncology, is an adverse prognostic feature, as is the mediastinum site, which is another powerful prognostic factor in the pediatric and adult experience.^12,16 Our statistical analysis resulted in a model that identified three prognostic groups among children with localized, nonmetastatic tumors: (1) good prognosis patients with localized gonadal or retroperitoneal primary sites and AFP levels less than 10,000 ng/mL (3-year FFS rate, 100%), (2) intermediate prognosis patients with extensive nonmetastatic primary sites and AFP levels less than 10,000 ng/mL or nongonadal nonretroperitoneal localized primary sites with AFP levels less than 10,000 ng/mL (3-year FFS rate, 81%), and (3) poor prognosis patients with AFP levels greater than 10,000 ng/mL or advanced nonretroperitoneal nongonadal primary sites (3-year FFS rate, 43%).

This is the first study to suggest the independent prognostic significance of AFP level and location of the primary site with regard to treatment failure in pediatric GCTs. The aim of our analysis was to assess prognostic variables among patients with localized disease, and we did not include data from metastatic patients. In general, metastatic patients are empirically considered to be poor prognosis patients and are treated more intensively in pediatric protocols. International collaboration is required to conduct a multivariate analysis of prognostic factors, including both metastatic and nonmetastatic patients as well as other histologic types.

The clinical value of a three-group stratification has been proven for adults.¹⁶ Clinical trials are currently exploring new strategies designed to reduce toxicity in good prognosis patients or improve the cure rate of intermediate and poor prognosis patients using intensive and high-dose chemotherapy, respectively. In the pediatric age group, the use of a prognostic classification raises the possibility of tailoring the treatment according to clinical and biologic characteristics and of comparing data from cooperative groups using the same parameters. It is not certain that the same stratification is of clinical importance in pediatric GCTs. This question has led to the formation of an international collaborative group that comprises clinicians from the Childrens' Cancer Study Group, the Pediatric Oncology Group, the United Kingdom Children's Cancer Study Group, the German, Italian, and Nordic Societies of Pediatric Oncology, and SFOP. The aim of this collaboration is to confirm these data and to reach a consensus with significant implication in the management of this complex tumor entity. This may allow the identification of treatment strategies, in particular for the high-risk group of patients for whom the role of high-dose chemotherapy remains ill defined.

	ACKNOWLEDGMENTS

 
We thank Dr H.H. Mahmoud and Professor Pinkerton for their valued comments and helpful review.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
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Submitted September 21, 1998; accepted December 15, 1998.

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