# Outcome and late effects of patients treated for childhood vaginal malignant germ cell tumors

Robin Coppin, Hélène Martelli, Cyrus Chargari, Hélène Sudour-Bonnange, Daniel H. Orbach, Cécile Vérité, Marlène Pasquet, Laure Saumet, Christophe Piguet, Catherine Patte, et al.

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## To cite this version:

Robin Coppin, Hélène Martelli, Cyrus Chargari, Hélène Sudour-Bonnange, Daniel H. Orbach, et al. Outcome and late effects of patients treated for childhood vaginal malignant germ cell tumors. Pediatric Blood and Cancer, 2023, 70 (12), 10.1002/pbc.30697. hal-04271278

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Distributed under a Creative Commons CC BY 4.0 - Attribution - International License
DOI: 10.1002/pbc.30697

Pediatric
Blood &
Cancer

<figure><img src="image_3.png" /></figure>

aspho
The American Society of
Pediatric Hematology/Oncology

WILEY

RESEARCH ARTICLE

# Outcome and late effects of patients treated for childhood vaginal malignant germ cell tumors

Robin Coppin<fnref n="1" /> ID

Helene Martelli<fnref n="2" />

Cyrus Chargari<fnref n="3" />

Helene Sudour-Bonnange<fnref n="4" /> ID

Daniel Orbach<fnref n="5" /> ID

Cecile Vérité<fnref n="6" />

Marlene Pasquet<fnref n="7" />

Laure Saumet<fnref n="8" />

Christophe Piguet<fnref n="9" />

Catherine Patte<fnref n="1" />

Florent Guérin<fnref n="2" /> ID

Cecile Faure-Conter<fnref n="10" /> ID

Brice Fresneau<fnref n="1" />,<fnref n="11" /> ID

Correspondence

Brice Fresneau, Department of Pediatric
Oncology, Gustave Roussy, 114 rue Edouard
Vaillant, 94805 Villejuif, France.

Email: brice.fresneau@gustaveroussy.fr

Abstract

**Purpose:** Vaginal malignant germ cell tumors (MGCT) are rare, occurring in children less than 2 years old and raise the question of the optimal local treatment.

**Methods:** We included children treated for vaginal MGCT according to the French TGM-95/2013 regimen. Patients were classified as standard risk (SR: localized disease and alpha-fetoprotein (AFP) < 10,000 ng/mL) or high risk (HiR: metastatic and/or AFP > 10,000 ng/mL) and were treated, respectively, with three to five VBP (vinblastine-bleomycin-cisplatin) or four to six VIP (etoposide-ifosfamide-cisplatin), followed by conservative surgery and/or brachytherapy in case of post-chemotherapy residuum.

**Results:** Fourteen patients were included (median age = 12 months), of which six (43%) were classified as HiR. AFP levels were normalized after first-line chemotherapy in all cases but one. A vaginal post-chemotherapy residuum (median size = 8 mm, range: 1-24 mm) was observed in 13/14 patients, treated by complete resection in seven of 13

**Abbreviation:** AFP, Alpha-Feto-Protein; COG, children oncology group; CT, compute tomography; EFS, event free survival; eGFR, estimated glomerular filtration rate; HiR, high risk group; JEB, carboplatin-etoposide-bleomycin regimen; MGCT, malignant germ cell tumor; MRI, magnetic resonance imaging; OS, overall survival; PEB, cisplatinum-etoposide-bleomycin regimen; SFCE, french society of pediatric oncology; SR, standard risk group; VBCA, vinblastine-bleomycin-carboplatin-doxorubicin regimen; VBP, vinblastine-bleomycin-cisplatinum regimen; VIP, etoposide-ifosfamide-cisplatinum regimen.

This is an open access article under the terms of the [Creative Commons Attribution-NonCommercial License](https://creativecommons.org/licenses/by-nc), which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

© 2023 The Authors. Pediatric Blood & Cancer published by Wiley Periodicals LLC.

<footnote n="1">¹Department of Children and Adolescents Oncology, Gustave Roussy, Paris-Saclay University, Villejuif, France</footnote>

<footnote n="2">²Department of Pediatric Surgery, Bicêtre Hospital - Assistance Publique-Hôpitaux de Paris - Université Paris Saclay, Le Kremlin-Bicêtre, France</footnote>

<footnote n="3">³Department of Radiation Therapy, Gustave Roussy, Paris-Saclay University, Villejuif, France</footnote>

<footnote n="4">⁴Department of Pediatric Oncology and AYA Unit, Centre Oscar Lambret, Lille, France</footnote>

<footnote n="5">⁵SIREDO Oncology Center (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer) Institut Curie, PSL University, Paris, France</footnote>

<footnote n="6">⁶Department of Pediatric Onco-Hematology, Centre Hospitalier Universitaire, Bordeaux, France</footnote>

<footnote n="7">⁷Department of Pediatric Onco-Hematology, Centre Hospitalier Universitaire, Toulouse, France</footnote>

<footnote n="8">⁸Department of Pediatric Onco-Hematology, Centre Hospitalier Universitaire, Montpellier, France</footnote>

<footnote n="9">⁹Department of Pediatric Onco-Hematology, Centre Hospitalier Universitaire, Limoges, France</footnote>

<footnote n="10">¹⁰Department of Pediatric Oncology, Institut d'Hemato-Oncologie Pediatrique, Lyon, France</footnote>

<footnote n="11">¹¹Paris-Saclay University, Paris-Sud University, Epidemiology of Radiation, CESP, INSERM, Villejuif, France</footnote>
(viable cells in three of seven), incomplete resection in four of 13 (viable cells in two of four), with adjuvant brachytherapy in two of 13, and exclusive brachytherapy in two of 13 (viable cells in one of six). Among the six patients with viable disease, four patients received adjuvant chemotherapy. One patient (SR) experienced immediate postoperative relapse despite presenting no viable residual cells and was treated with four VIP cycles and brachytherapy. At last follow-up (median = 4.6 years, range: 0.5-16), all patients were alive in complete remission. Five patients suffered from vaginal sequelae with synechiae and/or stenosis (of whom four had undergone brachytherapy).

**Conclusion:** Childhood vaginal MGCTs show a highly favorable prognosis with risk-adapted chemotherapy and local treatment of post-chemotherapy residuum (preferably by conservative surgery with partial vaginectomy). Brachytherapy could be an alternative when conservative surgery is not deemed possible or in cases of incomplete resection with residual viable cells.

KEYWORDS

alpha-fetoprotein, brachytherapy, children, germ cell tumors, surgery, vaginal tumors

# 1 | INTRODUCTION

Malignant germ cell tumors (MGCT), with an annual incidence of two to three per million children, contribute to 3%-5% of malignancies in patients under the age of 15 years.¹,² Vaginal MGCTs are very rare, with a relative incidence of 2% among pediatric MGCTSs. They primarily occur in children under 2 years old, and are histologically characterized by a yolk sac tumor, with or without an associated teratoma component.³ Conversely to other extragonadal MGCTs such as sacrococcygeal, mediastinal, and retroperitoneal tumors, vaginal MGCTs have an overall favorable prognosis when treated with a combination of cisplatinum-based chemotherapy and local treatment.⁴ However, these treatments can have late-onset effects: cisplatin exposes children to renal dysfunction and hearing loss, especially in the very young, whereas local treatment with surgery and/or radiotherapy can lead to fertility issues and alteration of sexual quality of life.⁵ Vaginal MGCTs are so rare that existing literature comprises mainly of case series, reporting survival but lacking information on long-term health outcomes.

We report a prospective national series of vaginal MGCTs treated in France over 20 years (1995-2019) in the two consecutive national germ cell tumor (GCT) studies (TGM-95 and TGM-2013), with a focus on the therapeutic advances in terms of local treatments, survival benefits, and updated long-term follow-up data regarding toxicity induced by platinum salts and local treatments.

# 2 | PATIENTS AND METHODS

## 2.1 | Patients

Between 1995 and 2019, French patients aged 18 years and younger with extracranial non-seminomatous MGCTs were enrolled in two

consecutive prospective nonrandomized studies, TGM-95 (1995-2005)⁶ and TGM-2013 (2013-2019). All patients treated for vaginal MGCTs in these studies, as well as patients referred to Gustave Roussy in first-line in the inter-study period, were included in this study.

## 2.2 | Treatment recommendations and risk stratification

In the TGM-95 and TGM-2013 studies, preoperative chemotherapy was advised for cases of vaginal MGCTs, as immediate surgery allowing both complete and conservative resections was deemed unfeasible. Two risk groups were established: standard risk (SR) with initial alpha-fetoprotein (AFP) less than 15,000 ng/mL (TGM-95) or 10,000 ng/mL (TGM-2013) and absence of metastasis, and high-risk (HiR) with initial AFP higher than 15,000 ng/mL (TGM-95) or 10,000 ng/mL (TGM-2013) and/or metastatic disease. For the SR group, VBP (vinblastine-bleomycine-cisplatin) regimen was delivered, whereas in HiR group, VIP (etoposide-ifosfamide-cisplatin) regimen was used (Table 1). The number of courses varied in TGM-95, from three to five courses of VBP and four to six courses of VIP, including two courses after tumor marker normalization, whereas the total number of courses was fixed at four (VBP or VIP) in TGM-2013. In the absence of tumor marker normalization after four courses or in case of progression/relapse (defined as confirmed AFP increase on successive measurements and/or radiological progression of a residual lesion and/or a new lesion), if VBP was administered as first-line treatment, patients were switched to a VIP regimen; if VIP was administered as first line, bleomycin-carboplatin-adriamycin was recommended as the rescue regimen.⁶

Local treatment was recommended in the case of post-chemotherapy residuum, involving complete resection of the vaginal
<table><caption>TABLE 1 Chemotherapy regimens used in the two French clinical studies for malignant germ cell tumors TGM95 and 2013.</caption><thead><tr><th></th><th>Clinical study</th><th>Drugs</th><th>Day 1</th><th>Day 2</th><th>Day 3</th><th>Day 4</th><th>Day 5</th></tr></thead><tbody><tr><td rowspan="10">SR</td><td rowspan="3">TGM95 (&gt;1 year and &gt;10 kg)</td><td>VINBLASTIN 3 mg/m²/day</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>BLEOMYCIN 15 mg/m²/day</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>CISPLATINUM 100 mg/m²/day</td><td></td><td></td><td>x</td><td></td><td></td></tr><tr><td rowspan="3">TGM2013 (&gt;1 year and &gt;10 kg)</td><td>VINBLASTIN 3 mg/m²/day</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>BLEOMYCIN 15 mg/m²/day</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>CISPLATINUM 33 mg/m²/day</td><td></td><td></td><td>x</td><td>x</td><td>x</td></tr><tr><td rowspan="3">TGM95 (&lt;1 year and/or &lt;10 kg)</td><td>VINBLASTIN 0.1 mg/kg/day</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>BLEOMYCIN 0.5 mg/kg/day</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>CISPLATINUM 3.3 mg/kg/day</td><td></td><td></td><td>x</td><td></td><td></td></tr><tr><td rowspan="3">TGM2013 (&lt;1 year and/or &lt;10 kg)</td><td>VINBLASTIN 0.1 mg/kg/day.</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>BLEOMYCIN 0.5 mg/kg/day.</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>CISPLATINUM 1.1 mg/kg/day</td><td></td><td></td><td>x</td><td>x</td><td>x</td></tr><tr><td rowspan="5">HiR</td><td rowspan="3">TGM2013/95 (&gt;1 year and &gt;10 kg)</td><td>ETOPOSIDE 75 mg/m²/day</td><td>x</td><td>x</td><td>x</td><td>x</td><td>x</td></tr><tr><td>IFOSFAMIDE 3 g/m²/day</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>CISPLATINUM 20 mg/m²/day</td><td>x</td><td>x</td><td>x</td><td>x</td><td>x</td></tr><tr><td rowspan="3">TGM2013/95 (&lt;1 year and/or &lt;10 kg)</td><td>ETOPOSIDE 2.5 mg/kg/day</td><td>x</td><td>x</td><td>x</td><td>x</td><td>x</td></tr><tr><td>IFOSFAMIDE 0.1 g/kg/day</td><td>x</td><td>x</td><td></td><td></td><td></td></tr><tr><td>CISPLATINUM 0.65 mg/kg/day</td><td>x</td><td>x</td><td>x</td><td>x</td><td>x</td></tr></tbody></table>

Abbreviations: HiR, high risk; SR, standard risk.

<figure><img src="image_4.png" /><figcaption>FIGURE 1 Abdominal per-operative view of a post-chemotherapy residuum of a malignant germ cell tumor (MGCT) of the fornix treated by partial vaginectomy.</figcaption></figure>

residuum. This allowed both histological analysis and to attain complete remission. Surgery was performed either with an abdominal (tumors of the upper part of the vagina) or with a perineal approach (lower part). The surgical conservative procedure consisted of a partial vaginectomy with subsequent reconstruction, aiming to prevent vaginal stenosis. Tumors of the fornix were resected without uterine cervix resection, thus avoiding trachelectomy (Figure 1). If complete resection was not achievable with conservative surgery, brachytherapy was performed either as an adjuvant treatment following incomplete resection or as a standalone treatment. Brachytherapy was administered using the vaginal mold applicator technique.⁷ Before 2005, Iridium-192 wires were used to deliver a total dose of 60 Grays (Gy) administered through continuous low-dose irradiation

(dose rate < 0.5 Gy/h). The dose of 60 Gy is based on historical data on brachytherapy for pediatric vaginal tumors, in the context of potentially radio-resistant tumors. This dose was delivered to small residual volumes. Treatment was planned on radiographs. From 2005 onwards, irradiation was delivered through an Iridium-192 stepping source, delivering hourly pulses of 0.42 Gy. Treatment was planned on computed tomography (CT) ± magnetic resonance imaging (MRI). In both situations, the targeted volume consisted of the residual extent of disease, determined from clinical assessment (under general anesthesia), imaging data, and histopathological reports.⁸,⁹

## 2.3 | Data collection

Demographic information, tumor characteristics, cancer treatments, and long-term follow-up data regarding gonadal, sexual, renal, and hearing dysfunctions were collected. Renal dysfunction was defined as an altered estimated glomerular filtration rate (eGFR < 90 mL/min/1.73 m²), calculated using the CKD-EPI equation for adults and Schwartz formula for children. Clinically significant hearing dysfunction was defined as bilateral sensorineural loss of Brock grade ≥ 2 (–40 dB at 4000 Hz) on pure-tone audiometry. All toxicities were graded based on the NCI-CTCAE version 5.0. Consent for TGM-95/2013 trials entry as well as data computerization was obtained from parents/guardians according to national research ethics requirements.
## 3 | STATISTICAL METHODS

Event-free survival (EFS) was selected as treatment efficacy outcome, defined as the period from time of diagnosis to first occurrence of progression, relapse, last patient contact, second malignancy, or all-cause mortality (whichever occurred first). Overall survival (OS) was defined as time elapsed from date of diagnosis to death from any cause or last patient contact, whichever occurred first. Survival curves were calculated using the Kaplan-Meier method, and confidence intervals were computed with the Rothman method. Median follow-up duration was estimated using the Schemper method. All statistical tests were two-sided, with significance (alpha) set to .05. R 3.6.2 (http://www.R-project.org) was used for the statistical analyses.

## 4 | RESULTS

### 4.1 | Patient characteristics

Overall, 14 females treated for vaginal MGCTs in France between 1995 and 2019 were included. Clinical characteristics, treatment modalities, and survival outcomes are detailed in Table 2. The median age at the time of diagnosis was 12 months (range: 6–20), with vaginal bleeding as the initial symptom in all cases. Tumor marker AFP was increased at diagnosis in all patients (median AFP value 3260 ng/mL, range: 571–71,000), and was higher than 10,000 ng/mL in four cases (29%). In very young girls (under 1 year old), for whom AFP threshold was difficult to establish due to physiologically high levels, a systematic biopsy was recommended under vaginoscopy to confirm the diagnosis (13/14 in our study). Median tumor long axis was 39 mm (range: 24–80). Locoregional or metastatic spread was observed in four cases: two patients had lymph node invasion, including one with uterine spread, while the two others had lung metastases, including one case of rectal spread. Amongst the patients, eight were classified as standard risk and six as high risk: four due to an initial AFP value higher than 10,000 ng/mL and two with lung metastases. The four patients with extra-vaginal dissemination were in the HiR group due to either metastases or AFP higher than 10,000 ng/mL.

### 4.2 | Neoadjuvant chemotherapy

All patients underwent neoadjuvant chemotherapy, according to study guidelines and risk-group categorization: VBP in the eight SR cases (three cycles in one patient, four cycles in four patients, five cycles in three patients), while six HiR cases received VIP (four cycles in two patients, five cycles in four patients). Following first-line chemotherapy, complete biological remission with AFP normalization was achieved in 13/14 patients (93%). This included the two patients with lung metastases, which were radiologically cleared by chemotherapy. One patient did not achieve AFP normalization after four cycles of VBP (AFP = 137 ng/mL at 15 months of age), but showed no disease

<table><caption>TABLE 2 Characteristic of patients with vaginal malignant germ cell tumors (MGCT).</caption><thead><tr><th>Characteristics</th><th>No. (%)<br>14 patients</th></tr></thead><tbody><tr><td>Age at diagnosis (months)</td><td></td></tr><tr><td>Median</td><td>12</td></tr><tr><td>Risk stratification</td><td></td></tr><tr><td>Standard risk</td><td>8 (57%)</td></tr><tr><td>High risk</td><td>6 (43%)</td></tr><tr><td>AFP at diagnostic (ng/mL)</td><td></td></tr><tr><td>AFP &lt; 10,000</td><td>10 (71%)</td></tr><tr><td>AFP &gt; 10,000</td><td>4 (29%)</td></tr><tr><td>Metastatic extension</td><td></td></tr><tr><td>Lung</td><td>2 (14%)</td></tr><tr><td>First-line chemotherapy</td><td></td></tr><tr><td>VIP</td><td>6 (43%)</td></tr><tr><td>VBP</td><td>8 (57%)</td></tr><tr><td>Response to first-line chemotherapy</td><td></td></tr><tr><td>AFP normalization</td><td>13 (93%)</td></tr><tr><td>Vaginal post-chemotherapy residuum</td><td>13 (93%)</td></tr><tr><td>Local therapy</td><td></td></tr><tr><td>Exclusive surgery</td><td>9 (70%)</td></tr><tr><td>Exclusive brachytherapy</td><td>2 (15%)</td></tr><tr><td>Combined surgery and brachytherapy</td><td>2 (15%)</td></tr><tr><td>No local therapy</td><td>1 (7%)</td></tr><tr><td>Results of local therapy</td><td></td></tr><tr><td>Complete resection without viable tumor</td><td>4 (31%)</td></tr><tr><td>Complete resection with viable tumor cells</td><td>3 (23%)</td></tr><tr><td>Incomplete resection without viable tumor cells</td><td>2 (15%)</td></tr><tr><td>Incomplete resection with viable tumor cells</td><td>2 (15%)</td></tr><tr><td>Exclusive brachytherapy with viable tumor cells</td><td>1 (8%)</td></tr><tr><td>Exclusive brachytherapy without viable tumor cells</td><td>1 (8%)</td></tr><tr><td>Adjuvant treatment</td><td></td></tr><tr><td>Adjuvant VIP</td><td>3 (21%)</td></tr><tr><td>Adjuvant VBCA</td><td>1 (7%)</td></tr><tr><td>Malignant events</td><td></td></tr><tr><td>Relapse</td><td>1 (7%)</td></tr><tr><td>Median follow-up [range]</td><td>4.6 years<br>[0.5–16]</td></tr><tr><td>5-year EFS</td><td>93%</td></tr><tr><td>5-year OS</td><td>100%</td></tr></tbody></table>

Abbreviations: AFP, alpha-fetoprotein; EFS, event-free survival; OS, overall survival; VBCA, vinblastine-bleomycin-carboplatin-doxorubicin regimen; VBP, vinblastine-bleomycin-cisplatin; VIP, etoposide-ifosfamide-cisplatin.
progression on imaging, and received four additional cycles of VIP, resulting in secondary AFP normalization (AFP = 5 ng/mL).

## 4.3 | Local treatment

A vaginal post-chemotherapy residuum was observed at vaginoscopy in 13/14 patients (eight SR/five HiR), with a median size of 8 mm (range: 1-24). Only one patient achieved a complete macroscopic remission and consequently did not receive any local treatment.

Local treatment was performed in all 13 cases with post-chemotherapy residuum. Eleven patients were treated with limited conservative surgery: complete resection by partial vaginectomy for seven patients (two HiR/five SR) with viable cells in three of seven (one HiR/two SR), microscopic incomplete resection by partial vaginectomy for one patient (one SR) with viable cells, and excision biopsy under vaginoscopy for three patients (one HiR/two SR) with viable cells in one of three (one SR). Two patients received complementary brachytherapy due to incomplete resection with viable residual cells (two SR), with pulse dose rate technique and a total dose of 60 Gy during an average duration of 6 days. The two other patients (two HiR), with post-chemotherapy residuum, had no surgery because of a significant risk of fistula for one patient and persistence of extensive infiltration of the vaginal wall for the other one. These two patients were treated with exclusive brachytherapy with the previous modalities, both had a biopsy before and shown residual viable cells for one patient.

## 4.4 | Adjuvant chemotherapy

Among the six patients with viable tumor cells in post-chemotherapy residuum (four SR/two HiR), four patients (three SR/one HiR) received two courses of adjuvant chemotherapy (three VIP/one bleomycin-carboplatin-doxorubicin), because of incomplete microscopic resection (n = 1), limited free margins (n = 2), or large viable residuum (n = 1). Two patients (one SR/one HiR) did not receive adjuvant chemotherapy either after an incomplete microscopic resection of a viable post-chemotherapy residuum treated with adjuvant brachytherapy, or after a brachytherapy only on a viable post-chemotherapy residuum.

## 4.5 | Survival outcome and toxicities

After a median follow-up of 4.6 years (range: 0.5-16), only one patient had relapse. This patient had an initial SR disease, treated with four cycles of VBP and a complete resection of a post-chemotherapy residuum without viable malignant cells. Local paravaginal relapse occurred 2 months after the surgery, with AFP increase from normal range to 1300 ng/mL, and reached a second complete remission after four courses of VIP and brachytherapy. All other patients remained in first complete remission. The 5-year EFS and OS were estimated at 93% and 100%, respectively.

Regarding long-term toxicity, with a median age at last news of 8.5 years (range: 2-19), five patients had vaginal sequelae with

synechiae and/or stenosis (two grade-3: vaginal narrowing interfering with the use of tampons, sexual activity, or physical examination; and three grade-1: asymptomatic, mild vaginal narrowing), including the four treated with brachytherapy, three patients reported dysmenorrhea (one grade-2: moderate symptoms; and two grade 1: mild symptoms, intervention not indicated), and two patients had ototoxicity (Brock grade 1). No renal and gonadal toxicity was observed. Among the four patients aged 15 years and older at last news, all had spontaneous and regular menstrual cycles. It should be noted that among the five patients who were treated with brachytherapy, four had an ovarian transposition. No primary ovarian insufficiency was reported.

# 5 | DISCUSSION

We reported a prospective series of vaginal MGCT homogeneously treated over 20 years (1995-2019) according to national guidelines, with risk-adapted chemotherapy and local treatment with surgery and/or brachytherapy in cases of post-chemotherapy residuum. With such a strategy, the outcome was excellent with only one of 14 local relapse resulting in 5-year EFS and OS of 93% and 100%, respectively.

A neoadjuvant cisplatinum-based chemotherapy was systematically used in order to prevent or treat metastatic disease and to decrease tumor volume to allow conservative local treatment. In the SR group, the etoposide-free VBP regimen was chosen to limit acute and long-term mutagenic toxicities of this drug, whereas in the HiR group (metastatic or AFP > 10,000 ng/mL), the more intensive VIP regimen was preferred. In all cases except one, this first-line risk-adapted cisplatinum-based chemotherapy led to biological complete remission. However, in all cases except one, a post-chemotherapy residuum was observed, with viable malignant cells in 46% of cases (yolk sac tumor cells), without significant differences according to the chemotherapy regimen used (50% after VBP vs. 40% after VIP). However, when considering the overall burden of treatment, six of eight (75%) patients treated with VBP in the SR group received subsequent VIP chemotherapy or brachytherapy for biological non-remission, persistent viable residual disease or relapse, versus 33% of the patients treated with VIP. The use of VBP regimen in this extra-gonadal MGCT is consequently questionable and seems to be inadequate as an induction regimen, even if predicted long-term disease-free survival in nonmetastatic extragonadal MGCT occurring in children aged less than 11 years (including vaginal MGCT) is estimated to be higher than 90%.⁶,¹⁰ In our study, the VIP regimen seemed to have a better response rate. An alternative in SR vaginal MGCT would be the use of four cycles of standard-dose cisplatin combined with etoposide and low-dose bleomycin regimen (PEB).¹¹,¹² Replacing cisplatin by carboplatin would be another alternative.¹³,¹⁴ Comparative analyses of these trials are in favor of similar efficacy and toxicity of PEB and JEB,¹⁵,¹⁶ but this is actually prospectively evaluated in the international AGCT1531 randomized clinical trial (NCT03067181). For patients with HiR disease, VIP regimen appears to be very efficient, as previously reported in the overall TGM-95 analysis.⁶ A combined cisplatin and alkylating agents-based regimen was also tested by the Children's Oncology
<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /><figcaption>**FIGURE 2** Recommendations of the Germ Cell Tumor Group of the French Society of Pediatric Oncology (SFCE).</figcaption></figure>

Group (COG) in HiR GCT, with cyclophosphamide added to PEB regi-
men with overall good tolerance and efficacy.¹⁷ In our series, patients
with AFP higher than 10,000 ng/mL were considered as with HiR dis-
ease, but the most recent analyses did not confirm the poor prognostic
value of AFP at diagnosis in pediatric MGCT,¹⁰ contrary to adults
with metastatic MGCT.¹⁸ Consequently, taking into account the AFP
value at diagnosis for risk stratification of pediatric patients with non-
metastatic MGCT has to be debated, all the more than AFP rate is
sometimes difficult to interpret in very young patients (<1 year old).
Consequently, in these young children (<10 years old) with localized
vaginal MGCT classified as intermediate-risk disease in international
risk stratification for childhood MGCT, the PEB regimen could be
recommended, especially in cases with low AFP level at diagnosis
(<10,000 ng/mL). In cases with higher AFP secretion at diagnosis, the
question of the interest of using more intensive regimen such as VIP is
raised, as the advantage of VIP over PEB has not been studied in this
situation.

Concerning local treatment, in our series, all patients except one
had post-chemotherapy residuum, and consequently were treated
with surgery or excision biopsy and/or brachytherapy. Thanks to
chemotherapy, tumor residuum was small (8 mm in median) and acces-
sible in most cases to limited conservative surgery with complete
resection by partial vaginectomy or excision biopsy. These patients

treated with surgery as the only local treatment had very limited vagi-
nal sequelae, as only one developed post-operative vaginal synechia.
In a recent literature review of 136 cases of vaginal yolk sac tumor,
the proportion of patients treated with exclusive chemotherapy was
51% versus 7% in our series.¹⁹ But in this review, a wide propor-
tion of patients had suspected post-chemotherapy residuum disease
leading to biopsy and no further treatment in the absence of residual
viable malignant cells. For example, in the largest series, published by
Xie et al., among 17 patients treated for vaginal MGCT, 15 received
neoadjuvant chemotherapy, with suspected post-chemotherapy resid-
ual lesions in four patients who underwent vaginal biopsies, which were
negative for malignancy.²⁰ In the same manner, in the case series of
Terenziani et al. and Mayhew et al., two of four patients had suspected
post-chemotherapy residual lesions after four to six PEB cycles, leading
to biopsies without evidence of malignancy.¹⁹,²¹ In our series, a higher
proportion of patients, 43%, had viable malignant cells in residuum at
the end of first-line treatment. All these reports are concordant with
frequent post-chemotherapy residual lesions, which have to be docu-
mented with at least biopsies in order to identify viable malignant cells.
In cases of negative biopsies, a complementary surgery of residuum
could be omitted on the basis of the literature review. In cases of per-
sistent viable malignant cells in biopsies, we recommend to complete
local treatment with a conservative, organ-sparing surgery or, if not
feasible, to discuss the possibility of alternative local treatments such as brachytherapy. However, the risk of false-negative biopsies has to be debated. Consequently, in France, the recommendation of the Germ Cell Tumor Group of the French Society of Pediatric Oncology (SFCE) is to perform conservative resection of post-chemotherapy residuum by partial vaginectomy instead of biopsies whenever possible.

The role of brachytherapy has to be clarified in the treatment of vaginal MGCT. In this series, we report four patients treated with brachytherapy for incomplete microscopic resection with residual viable malignant cells or as the only local treatment. Local control disease was excellent in all cases. Consequently, brachytherapy seems to be a relevant alternative to surgery in vaginal MGCT. However, late effects of vaginal brachytherapy, especially synechiae and/or stenosis, which were observed in four of five patients (sequelae that can have a major impact on the quality of life) and ovarian insufficiency (even if it could be prevented by ovarian transposition²² as performed in four of five patients in our series), should restrict its use to cases with not feasible conservative surgical resection of post-chemotherapy residuum.²³ This strategy was previously developed for patients with vaginal rhabdomyosarcoma: in cases of complete histologically proven response after chemotherapy, it was shown that no further local treatment was necessary, whereas patients with residual disease were treated with brachytherapy in order to avoid non-conservative surgery or external radiotherapy for these tumors with usually large and multiple vaginal implantations.²⁴⁻²⁶ Contrary to rhabdomyosarcoma, residual lesions of vaginal MGCT are mostly unique, rarely infiltrative, with lonely vaginal implantation, leading in our experience to feasible conservative surgery in most cases.

The place of adjuvant chemotherapy remains debatable. In this series, 31% of the patients treated with local treatment received two courses of adjuvant chemotherapy for residual viable malignant cells, including one with microscopic incomplete resection, without relapse. However, two other patients with residual viable cells and microscopic incomplete resection or no resection were treated with brachytherapy without adjuvant chemotherapy and did not have relapse. On the other hand, one patient with a complete resection of a completely necrotic residuum who consequently did not receive adjuvant treatment had relapse. Consequently, in cases of post-chemotherapy residual viable malignant cells, adjuvant chemotherapy could be omitted if resection is complete or if resection is microscopically incomplete but associated with brachytherapy (Figure 2). In this last situation, the question of replacing brachytherapy by a second-line chemotherapy is raised, but according to our experience in vaginal MGCT relapses and other GCT primaries, we think that more intensive chemotherapy could not replace a good quality local treatment.

## 6 | CONCLUSION

Childhood vaginal MGCTs carry a very favorable prognosis with risk-adapted chemotherapy and local treatment. A post-chemotherapy vaginoscopy is necessary to identify any residual lesion. In cases of post-chemotherapy residuum, we recommend to remove it by con-

servative resection with partial vaginectomy whenever possible to achieve a complete resection of persistent viable residual cells in the residuum. Brachytherapy could be an alternative when conservative surgery is not deemed possible or in cases of incomplete resection of post-chemotherapy residuum with persistent viable residual cells. In cases of brachytherapy, gynecological long-term follow-up is necessary to detect and treat vaginal sequelae such as synechiae and stenosis.

## ACKNOWLEDGMENTS

Thanks to the investigators of the following French centers, which contributed patients to this study: Gustave Roussy (Villejuif), Institut Curie (Paris), Oscar Lambret (Lille), CHU Toulouse, Léon Bérard (Lyon), CHU Bordeaux, CHU Montpellier, and CHU Limoges. Thanks to Linglart L. for the English revision.

## CONFLICT OF INTEREST STATEMENT

The authors declare they have no conflicts of interest to disclose.

## DATA AVAILABILITY STATEMENT

No data are available.

## ORCID

Robin Coppin ID https://orcid.org/0009-0009-0590-5507

Helene Sudour-Bonnange ID https://orcid.org/0000-0002-1991-3585

Daniel Orbach ID https://orcid.org/0000-0002-2520-139X

Florent Guérin ID https://orcid.org/0000-0002-3487-3745

Cecile Faure-Conter ID https://orcid.org/0000-0002-4717-4943

Brice Fresneau ID https://orcid.org/0000-0001-7603-7828

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**How to cite this article:** Coppin R, Martelli H, Chargari C, et al. Outcome and late effects of patients treated for childhood vaginal malignant germ cell tumors. *Pediatr Blood Cancer*. 2023;70:e30697. https://doi.org/10.1002/pbc.30697