Intensive cisplatin and cyclophosphamide-based chemotherapy without radiotherapy for intracranial germinomas: failure of a primary chemotherapy approach

PURPOSE: High rates of overall and event-free survival have been reported in patients with intracranial germinomas treated with craniospinal radiotherapy. More recently, similar results have been reported with chemotherapy combined with radiotherapy to more localized treatment volumes. Our interest in exploring chemotherapy without radiotherapy in patients with CNS germinomas was based on concerns about the late sequelae of radiotherapy to the brain or neuraxis and also the well documented success of chemotherapy alone in patients with disseminated extracranial germinomas. The primary objective of this study was to determine whether intensive cisplatin and cyclophosphamide-based combination chemotherapy, without radiotherapy, was effective in patients with CNS germinomas. PATIENTS AND METHODS: Nineteen patients were enrolled, ranging in age from 1 to 24 years (median, 14 years). Thirteen were male. Nine had diabetes insipidus. Therapy comprised two courses of Regimen 'A' (cisplatin, etoposide, cyclophosphamide, and bleomycin) followed by MRI evaluation. Patients achieving a complete remission (CR) completed all planned therapy with two courses of regimen 'B' (carboplatin, etoposide, and bleomycin). Patients achieving less than a CR received two courses of Regimen 'B' followed by another evaluation. Those in CR after four courses of treatment received one additional course of Regimen 'A' and Regimen 'B', while those not in CR after four treatment courses underwent second look surgery and/or radiation therapy. RESULTS: Eleven of 11 patients with residual postoperative disease assessable for response achieved a CR. With a median follow-up of 6.5 years, eight out of 19 (0.42) patients remain in CR 1 without radiotherapy and another three patients are in stable second or subsequent remissions. Three patients died from treatment-related toxicity and another died in CR 1 from an uncharacterized leukoencephalopathy. The 5-year event-free survival (EFS) was 0.47 +/- 0.23 and 5-year overall survival (OS) was 0.68 +/- 0.22. CONCLUSIONS: Intensive cisplatin and cyclophosphamide-based chemotherapy was effective in achieving remissions, however, the long-term outcome using this treatment program was unsatisfactory and associated with unacceptable morbidity and mortality, particularly in patients with diabetes insipidus.     

Radiological pseudoprogression post‐radiotherapy in a child with pineal germ cell tumour

Little is known about pseudoprogression in brain tumours other than gliomas. A 9‐year‐old male child with a pineal teratoma/germinoma underwent surgical resection followed by adjuvant chemo‐radiotherapy. The magnetic resonance imaging scan 4 months post‐radiotherapy showed a contrast‐enhancing lesion within the surgical cavity suspicious of recurrence. These radiological findings subsequently resolved without any specific intervention. The child continues in remission 2 years post‐treatment. This case illustrates the occurrence of pseudoprogression post‐radiotherapy in intracranial GCT and highlights an unmet need for greater implementation of functional imaging techniques in paediatric neuro‐oncology to avoid undue discontinuation of effective treatments or inappropriate enrolment in clinical trials.     

Harmonica consensus,controversies, and future directions in radiotherapy for pediatric Wilms tumors

Radiotherapy (RT) is essential for multimodality treatment of pediatric renal tumors, particularly in higher-risk and metastatic disease. Despite decades of use, particularly for Wilms tumor, there remain controversies regarding RT indications, timing, dose, and targets. To align global management, we address these issues in this international HARMONIsation and CollAboration (HARMONICA) project. There are multiple knowledge gaps and opportunities for future research including: (1) utilization of advanced RT technologies, including intensity-modulated RT, proton beam therapy, combined with image-guided RT to reduce target volumes; (2) impact of molecular biomarkers including loss of heterozygosity at 1p, 16q, and 1q gain on RT indications; (3) mitigation of reproductive toxicity following RT; (4) promotion of RT late effects research; and (5) support to overcome challenges in RT utilization in low- and middle-income countries where 90% of the world's children reside. Here, we outline current status and future directions for RT in pediatric renal tumors.     

Survival and quality of life of paediatric intracranial germ cell tumour patients treated at the Christie Hospital, 1972–1993

From 1972 to 1993, 25 patients under 16 years old were treated at the Christie Hospital for intracranial germ cell tumours (ICGCTs). A retrospective analysis of the case notes was undertaken. The cases comprised 10 germinomas, nine non-germinomatous germ cell tumours (NGGCTs), and six cases with no histology. Ten patients had either complete or incomplete removal of the tumour. All patients received radiotherapy (20 patients received craniospinal irradiation [CSI]). Thirteen patients received chemotherapy at presentation (six platinum-based). All marker-negative pure germinomas treated with CSI survived. The actuarial 5-year survival for NGGCTs was 44%. Although CSI resulted in spine shortening, the overall effect on growth was not marked and the neuropsychologic sequelae were minimal with good overall functional results. © 1995 Wiley-Liss, Inc.     

Novel heterozygous mutation in the PTEN gene associated with ovarian germ cell tumor complicated by growing teratoma syndrome and overgrowth in a two‐year‐old female

Growing teratoma syndrome (GTS) is a condition in which mature teratoma with negative tumor markers arises at the site of a treated malignant germ cell tumor. Pathogenic variants in PTEN have been reported to cause autosomal dominant cancer predisposition syndromes and are associated with germ cell tumors. We report the association of a novel heterozygous pathogenic variant in PTEN and very early onset ovarian germ cell tumor complicated by GTS as well as overgrowth syndrome. This marks the youngest reported patient to have developed GTS following treatment of her primary malignant ovarian germ cell tumor.     

Pediatric malignant germ cell tumors: A comparison of the neuro‐oncology and solid tumor experience

Malignant germ cell tumors (GCT) arise from abnormal migration of primordial germ cells and are histologically identical whether they occur inside or outside the central nervous system (CNS). However, the treatment strategy for GCTs varies greatly depending on the location of the tumor. These differences are in part due to the increased morbidity of surgery in the CNS but may also reflect differential sensitivity of the tumors to chemotherapy and radiation therapy (RT) or not‐yet‐understood biologic differences between these tumors. Historically, specialists caring for extracranial and intracranial GCT in the United States have practiced separately without much cross communication. The focus of this review is a discussion of differences between the management of CNS and extra‐CNS GCTs and opportunities for collaboration and future research.     

Vaginal endodermal sinus tumor

Malignant germ cell tumors are rare tumors of childhood accounting less than 3% of pediatric malignancies, and endodermal sinus tumor (EST) is the most common histological subtype. The vagina is an extremely rare site for germ cell tumors (GCT). A one-year female was admitted with history of bleeding pervagina. She had pallor and a mass was palpable anteriorly on rectal examination. Magnetic Resonance Imaging (MRI) showed a tumor mass at the junction of cervix and vagina and biopsy was suggestive of a vaginal EST. The serum alpha fetoprotein (AFP) was elevated. She underwent vaginohysterectomy. The tumor was excisedin toto and patient received four courses of cisplatin, etoposide and bleomycin. At one year of follow up, patient was symptom free and serum AFP remained at normal level. EST of the vagina is a rare, highly malignant GCT that exclusively involves children less than 3 years of age. It is both locally aggressive and capable of metastasis. Even though more conservative surgery is advised to maintain sexual and reproductive function, at times, radical surgery is mandatory depending on the infiltration of the tumor to the surrounding structures. Simple tumor excision is not sufficient, as residual cells induce recurrence and make chemotherapy ineffective. The serum AFP level is a useful marker for diagnosis and monitoring the recurrence of vaginal EST in infants.