Outcomes of pediatric patients with malignant extracranial germ cell tumors at a tertiary care hospital in Mexico

Germ Cell Tumors (GCT) are the second most common malignancy in adolescence. Extracranial malignant GCT (eGCT) are much more common among adolescents, representing approximately 15% of cancer diagnoses in this age group. Treatment for these tumors involves surgery, chemotherapy, and radiotherapy. Total tumor resection is a primary prognostic factor. The most common treatment regimen consists of bleomycin, etoposide, and cisplatin. In Latin America, data are scarce. Some reports show that the most frequent age of presentation is in adolescents aged 15–19 years. A retrospective study was conducted from January 2014 to December 2024, accepting 60 newly diagnosed patients with malignant eGCT at a tertiary care hospital in Mexico. The chemotherapy regimens used were CISCA II and BEP. We performed descriptive statistics, as well as Kaplan–Meier survival analysis. The mean patient age was 10.5 + 4.5 years. The adolescent group was the most significant (48.3% of the total of all patients). The most common histology was mixed tumor in 35% of patients. The most frequent primary site was the gonadal region in 95% of patients; 53.3% of patients presented in advanced stages III and IV. The overall survival rate was 94.9%, and the relapse-free survival rate was 88.5%. Three deaths were recorded in 10 years. Five patients with hypoacusis were recorded, and in one case, a decrease in the LVEF was observed, with no change in functional class. In conclusion eGCT are highly curable diseases. In this series of cases, good long-term results were observed.

Germ Cell Tumors (GCT) are the second most common malignancy in adolescence, after Hodgkin lymphoma, and can occur in the gonads or extragonadal regions (1–3). Childhood extracranial malignant GCT (eGCT) can be divided into gonadal and extragonadal types.

Malignant germ cell tumors are classified histologically into three categories: seminomatous, non-seminomatous, and mixed.

Seminomatous tumors include seminomas (testes), dysgerminomas (ovaries), and germinomas (extragonadal tumors). They are rare in pediatrics, especially in their pure seminoma form, except for patients with sex chromosome abnormalities or cryptorchidism (4).

The beta subunit of human chorionic gonadotropin (hCG) is produced by dysgerminoma; however, dysgerminoma can be a tumor marker-negative tumor.

Non-seminomatous tumors include endodermal sinus tumors (also known as yolk sac tumors), choriocarcinoma, and embryonal carcinoma. For these, tumor marker testing is essential for diagnosis and prognosis: alpha-fetoprotein, hCG beta subunit, and lactate dehydrogenase (4, 5).

Staging is performed using the Children's Oncology Group (COG) system. In the case of ovarian tumors, the classification developed by the International Federation of Gynecology and Obstetrics (FIGO) is also considered (6).

Risk stratification is performed using the Malignant Germ Cell Tumors International Collaboration (MaGIC), which takes into account age at diagnosis (greater than or less than 11 years), location (ovary, testis, or extragerminal), and COG stage. Those classified as high risk have a survival rate of <70% due to a lower response to chemotherapy and disease progression (7).

Treatment for these tumors involves surgery, chemotherapy, and radiotherapy. Total tumor resection is the main prognostic factor and is part of the staging process used to decide whether to initiate chemotherapy treatment.

The most commonly used regimen consists of bleomycin, etoposide, and cisplatin, typically administered over six cycles. The dose has been reduced over the years, considering the adverse effects of these agents, which allows for a better quality of life during treatment and achieves therapeutic levels (6).

In Latin America, data are scarce and heterogeneous. Some reports show that the most frequent age of presentation is in adolescents aged 15–19 years (8).

In Argentina, in 2016, a series of 99 pediatric patients with extracranial GCT was reported at 10 years. The DFS and OS estimates for the whole group were 82% and 90%, respectively (9).

In Mexico, overall survival rates of 83.3% are reported in the Central-South Region, in a 2006–2012 cohort (10). Also, others report an incidence of malignant ovarian germ cell tumors three times higher than that observed in Western countries and the United States, with a peak incidence occurring in female adolescents and young women. In Mexico, the incidence of Dysgerminoma, yolk sac tumor, and mixed germ cell tumors makes up more than 90% of all malignant ovarian germ cell tumors (11).

At the Federico Gómez Children's Hospital of Mexico, the CISCA II regimen has been used since 1997 for patients with extracranial germ cell tumors. In recent years, given the global trend toward cutting-edge combination therapies for pediatric germ cell tumors, the first-line treatment for these patients was planned to be changed to the BEP regimen, based on the justification of lower toxicity while maintaining disease-free and overall survival rates. To address this need and make the most objective decisions possible, two retrospective studies were conducted at the hospital. The first study, from 1997 to 2012, included 66 patients and 271 cycles (an average of 4.1 per patient), with an overall survival rate of 93.2% at 193 months. It reported 78 WHO grade 3 and 4 toxicity events (primarily hematological and infectious), with only one patient experiencing ototoxicity and no patients exhibiting renal or cardiac toxicity (unpublished data). The satisfactory result led the Oncology Department to continue this chemotherapy regimen.

Here we present the analysis of our patients over the last 10 years.

Sources and methods of participant selection: From January 2014 to December 2024, 62 children and adolescents newly diagnosed with malignant extracranial germ cell tumors (eGCT) were admitted to a tertiary care hospital (Hospital Infantil de México Federico Gómez). Primary caregivers signed informed consent for their children to receive treatment.

Two patient records were excluded from the study after pathology confirmed that the lesions, initially thought to be malignant, were teratomas that did not require treatment in Oncology Department.

Eligibility criteria: Diagnosis of malignant extracranial GCT confirmed by pathology and follow-up until the initiation of oncological surveillance or death at Hospital Infantil de México Federico Gómez.

Methods of follow-up: A retrospective follow-up was conducted on the 60 patients who met the eligibility criteria. Each patient contributed their follow-up time to the statistical analysis.

Institutional treatment consisted of CISCA II chemotherapy regimen, which consists of cyclophosphamide (500 mg/m 2) and doxorubicin (37.5 mg/m 2) administered on days 1 and 2 of treatment, followed by cisplatin (90 mg/m 2) on day 3 of chemotherapy (12). The frequency of the cycles was every 3 weeks until the blood markers became negative. The cycle number in this study was in a range 2–6 according to the response.

The BEP regimen, on the other hand, involves bleomycin (15 U/m 2) administered on day 1 of treatment, along with etoposide (100 mg/m 2) and cisplatin (20 mg/m 2) administered from day 1 to day 5 of chemotherapy.

Adverse effects were documented. Audiometries were performed before and at the end of chemotherapy. Evaluation of cardiac function was monitored with an echocardiogram at the beginning and end of treatment.

Descriptive statistics were performed as well as Kaplan Meier survival analysis.

In this 10-year analysis, we obtained 60 medical records of patients diagnosed with extracranial GCT at a tertiary referral hospital in Mexico City, Mexico (Table 1).

The mean patient age was 10.5 + 4.5 years. The adolescent group was the largest, with 48.3% of the total of all study subjects. For every male there were 1.7 females in this study.

The most common histology was mixed tumor in 21 patients (35%), followed by dysgerminoma in 17 patients (28%), and yolk sac tumor in 16 patients (26%). The rarest histology types were choriocarcinoma in one patient (1.6%) and seminoma in one patient (1.6%).

The most frequently identified primary site was the gonadal region in 95% of patients, and the rarest was the retroperitoneal region in only one patient (1.6%).

46.6% of patients presented in early stages I and II, and the remaining 53.4% patients in advanced stages III and IV.

The chemotherapy regimens used were CISCA II in 88.3% of cases, BEP in one patient, and a combination of BEP/CISCA II in one patient.

Regarding overall survival (Figure 1), a 10-year survival rate of 94.9% was obtained.

The mean follow-up was 70.9 months, the median was 76 months, with a standard deviation of 34.5 months (minimum of 9 months and maximum of 134 months).

A stage-by-stage analysis reveals that stages I and II have 100% survival rates, stage III has a 93.3% survival rate, and stage IV has an 88.2% survival rate.

Relapse-free survival was 88.5% (with a total of 7 patients experiencing relapse over the 10 years).

Concerning adverse effects, three deaths were recorded in 10 years, 1 of which was due to septic shock, and two due to disease progression.

As for follow-up, on hearing function, five patients displayed hypoacusis, but none required the use of hearing aids.

In one case, a decrease in the left ventricle ejection fraction (LVEF) of more than 20% from baseline was observed, with no change in functional class.

Gonadal and extragonadal germ cell tumors are uncommon in childhood, with an incidence of 2.4 cases per million children. However, they constitute an essential clinical entity in pediatric oncology. In our 10-year follow-up study at a tertiary care hospital in Mexico, we reported an average of 7 cases per year; this does not include primary CNS germ cell tumors (13).

The mean age in this series of cases was 10.5 + 4.5 years. The adolescent group was the most significant (48.3% of the total of all patients).

Patients with eGCT have demonstrated high cure rates. This is due to the efficacy of cisplatin in combination with vinblastine and bleomycin (PVB). This was first documented at Indiana University in 1977, after demonstrating the antineoplastic activity of etoposide in patients with relapse. Etoposide, in combination with cisplatin and bleomycin (BEP), was superior to PVB, especially in patients with advanced germ cell tumors. Furthermore, BEP produced substantially less toxicity.

Given that survival rates are approximately 90% in patients with a good prognosis, the primary objective of new studies in this subgroup of patients is to reduce toxicity while maintaining efficacy.

In patients with a poor prognosis, the survival rate is approximately 50%, and the objective of current studies is to enhance treatment efficacy.

Other studies have attempted to modify the BEP regimen in patients with a good prognosis and have focused on reducing toxicity, initially by eliminating bleomycin from the different regimens. The Australian Germ Cell Trial Group (222 patients) randomized patients to receive cisplatin and etoposide with or without bleomycin. After 4 years of follow-up, disease-related mortality was 5% in patients receiving bleomycin and 15% in the group without bleomycin. Similarly, the EORTC and ECOG (Eastern Cooperative Oncology Group) evaluated the BEP vs. EP regimen. Both groups reported inferior results with EP compared to BEP, with survival rates in patients with a good prognosis of 86% vs. 95% (BEP). Likewise, the authors report that switching from cisplatin to carboplatin has been less effective (14).

In the early 1980s, a cyclic chemotherapy regimen combining two separately effective regimens (Cisplatin, doxorubicin, and cyclophosphamide (CISCA II) and vinblastine and bleomycin (VB) was developed at MD Anderson Cancer Center. Initial results with the CISCA/VB regimen in 48 patients indicated a 92% complete response rate. These encouraging results were subsequently confirmed in 1986 in an extensive study of 100 patients with advanced germ cell tumors, which achieved a long-term recurrence-free survival rate of 89%. This study concluded that the CISCA/VB regimen is highly effective in patients with germ cell tumors. However, some reports of questionable toxicity have been reported (15).

According to a study by Logothetis et al. (12) 100 patients with advanced mixed germ cell tumors were treated with cisplatin, cyclophosphamide, and doxorubicin (CISCA II), alternating with vinblastine and bleomycin (VB). The overall survival rate was 89%, and the disease-free rate was 86%. This was 92% in survivors of patients with gonadal cancer and only 56% in patients with extragonadal tumors. The acute toxicity reported in this study is noteworthy: 45% of the cycles with BV were associated with grade I oral toxicity; 39% with grade II toxicity; and 3% with grade III toxicity.

With the CISCA regimen, 19% reported grade I oral toxicity, 4% with grade II, and 0.7% with grade III, much lower than with the VB regimen.

Six percent of patients reported reversible renal toxicity, in all cases apparently secondary to platinum. Hearing loss occurred in 3% of patients, and tinnitus persisted in 2% of patients. Ten percent of patients with BV developed peripheral neuropathy.

Cardiac toxicity occurred in 1% of patients with CISCA, which was completely reversible, and the significant decrease in ejection fraction subsequently normalized.

One death was reported, indicating that both regimens are well tolerated. This death was related to the use of chemotherapy in a patient who was an unrecognized drug user, who developed aspiration pneumonia, candidemia, and alcoholic hepatitis during myelosuppression and died (12).

In another study, Culine et al. (16) compared treatment with BEP vs. CISCA II/VB in patients with high-risk nonseminomatous germ cell tumors. They analyzed 17 patients who received the CISCA II/VB protocol and observed three premature deaths, four primary failures, 10 complete responses, two relapses, and one acute myeloid leukemia. Fifty-three percent of patients were disease-free 15–38 months after completing treatment. In the BEP group, there was one early death, one primary failure, one death due to toxicity, one partial response, and 19 complete responses, with a significant number of 8 relapses. Seventy percent remain disease-free between 26 and 52 months after completing treatment.

Myelosuppression and mucositis were clearly more frequent in the CISCA II/VB regimen; however, no sepsis-related deaths were reported. One patient died of septic shock after the fourth cycle of BEP. Grade IV thrombocytopenia was reported in 26% of cases treated with the CISCA regimen. It is noteworthy that no cardiac toxicity was reported. In this study, the survival rate was 62.5%; better outcomes were achieved in patients treated with the BEP protocol, with a survival rate of 76% compared to 56% for the CISCA II/VB regimen. However, patients receiving the latter regimen (CISCA II) had more advanced disease, and a higher proportion of patients had an extragonadal primary tumor (16).

In this study, we report a 10-year experience in a Mexican hospital using CISCA II protocol, with limited toxicity in our results and improved efficacy in patients with advanced disease, with an overall 10-year survival rate of 94.9%.

In our results presented here, limited toxicities were observed; cardiac toxicities were reported in only one patient, with no impact on functional status. Therefore, in addition to our report of high survival rates and this limited toxicity, we consider this a suitable chemotherapy option for patients with germ cell tumors, especially those with high-risk and extragonadal tumors.

It is clear that outcomes for patients with metastatic germ cell tumors have improved; the long-term toxicity that frequently characterizes chemotherapy has become more critical in the face of such a high cure rate. Physicians must identify patients and select treatment so that those who require intensive chemotherapy can be identified. At the same time, those with a more favorable prognosis can receive less aggressive but equally effective therapy.

Some limitations regarding the external validity of this work are due to the sample size. Furthermore, the assessment of long-term effects (fertility, renal, and pulmonary) was not conducted. These longer-term effects should be studied in well-established survivorship clinics, even if the patients are older than 18 years old and remain in pediatric care centers.

The above considerations should be taken into account in future studies in which regional collaborative groups can be formed.

This work presents a case series with adequate survival rates, comparable to those achieved internationally, and limited toxicity in a middle-income country.