Outcome of premature infants treated with chemotherapy for neuroblastoma in France.

Outcome of premature infants treated with chemotherapy for neuroblastoma in France. | Authorea try { document.documentElement.classList.add('js'); } catch (e) { } var _gaq = _gaq || []; _gaq.push(['_setAccount', 'G-8VDV14Y67G']); _gaq.push(['_trackPageview']); (function() { var ga = document.createElement('script'); ga.type = 'text/javascript'; ga.async = true; ga.src = ('https:' == document.location.protocol ? 'https://ssl' : 'http://www') + '.google-analytics.com/ga.js'; var s = document.getElementsByTagName('script')[0]; s.parentNode.insertBefore(ga, s); })(); Skip to main content Preprints Collections Wiley Open Research IET Open Research Ecological Society of Japan All Collections About About Authorea FAQs Contact Us Quick Search anywhere Search for preprint articles, keywords, etc. Search Search ADVANCED SEARCH SCROLL Pediatric Blood & Cancer This is a preprint and has not been peer reviewed. Data may be preliminary. 17 June 2025 V1 Latest version Share on Outcome of premature infants treated with chemotherapy for neuroblastoma in France. Authors : Dana AL KHALIFA [email protected] , Pascal Chastagner , Gudrun Schleiermacher 0000-0002-0133-5879 , and Lejeune J Authors Info & Affiliations https://doi.org/10.22541/au.175016310.00566920/v1 Published Pediatric Blood & Cancer Version of record Peer review timeline 379 views 241 downloads Contents Abstract Information & Authors Metrics & Citations View Options References Figures Tables Media Share Abstract Neuroblastoma is the most common solid extracranial tumor in children, and congenital forms account for 5% of all neuroblastoma cases. Diagnosis in utero is very rare, and their evolution leading to premature delivery for urgent treatment is exceptional. In some of these cases, chemotherapy is required after birth, in the face of tumor progression that threatens functional (dumbbell neuroblastoma), or even vital prognosis (stage 4S). However, the optimal doses of chemotherapy in premature newborns are not known. In this article, we review the management of six patients treated in French pediatric oncology centers, in order to analyze the treatment modalities, and report on their tolerance as well as the outcome of these newborns. Introduction Neuroblastoma is an embryonal tumor derived from the embryonic sympathetic nervous system, corresponding to the neural crest cells that normally migrate to form the adrenal medulla and sympathetic ganglia. It is the most frequent extracranial solid tumor in young children, and above all the most frequent malignant tumor in fetuses and infants. Its presentation is heterogeneous, and its evolution ranges from the possibility of spontaneous regression without chemotherapy to tumor progression that threatens functional and/or vital prognosis despite intensive treatment. It is sometimes diagnosed during the third trimester of pregnancy, requiring rigorous ultrasound monitoring. In most cases, there is no risk to the mother or fetus, and delivery takes place at or near term. Exceptionally, in utero evolution may necessitate premature delivery, particularly in cases of spinal cord compression or voluminous liver metastases, in order to initiate treatment. The aim of this article is to review the treatment and outcome of progressive neuroblastoma in children born prematurely in France. Patients and method This is a multicenter retrospective study of neuroblastoma patients treated over a period of eight 8 years in France. In order to collect all cases of premature children treated for neuroblastoma in French pediatric oncology centers, all these centers were surveyed, as well as the national childhood cancer registry. Unfortunately, data on prematurity are not available in this registry. Files were studied retrospectively, both electronically and non-electronically. Patient characteristics, including reasons for prematurity and institution of treatment, as well as details of treatment and outcome, were collated from records in four French centers. Results Six cases were identified, all eligible for the study, between 2018 and 2024. For the majority of our patients, histological confirmation of the primary tumor was missing due to the severity of the functional and/or vital prognosis and the clinical presentation, which left no doubt about the histology. Two patients had an intrathoracic paravertebral tumor (dumbbell neuroblastoma) with extension through the vertebral foramina which led to premature delivery, four had stage 4S neuroblastoma. Presentation, treatments and outcomes were as follows (Tables 1, 2, 3): Case 1 A female child was delivered by emergency caesarean section at 34 weeks’ gestation and 6 days due to an abnormal fetal heart rhythm. Clinical examination revealed enlarged hepatomegaly and collateral venous circulation. Ultrasound showed a left adrenal mass, heterogeneous hepatomegaly with multiple hyperechoic areas compatible with stage 4S neuroblastoma, and splenomegaly. Bone marrow aspiration revealed massive infiltration by neuroblasts. After intubation and assisted ventilation, the patient was transported to the operating room for an offloading laparotomy due to excessive increase in intra-abdominal pressure and respiratory failure. Chemotherapy was initiated on the first postnatal day, with etoposide without carboplatin, due to the presence of acute renal failure and anuria. Abdominal computed tomography (CT) scan after the first course of chemotherapy showed regression of the adrenal mass and stable nodular hepatomegaly. Local adrenalectomy was performed two weeks later, with major difficulty in closing the abdominal wall. The second course of chemotherapy began one week later with carboplatin/etoposide. The course was complicated by grade 4 neutropenia and thrombocytopenia, and a methicillin-resistant staphylococcus aureus blood infection. Despite this emergency treatment, ultrasonography after the second course showed increased peritoneal effusion, a stable-looking multinodular liver and an adrenal hematoma. The baby was pronounced dead at 34 days of age due to mechanical ventilation difficulties associated with intraperitoneal effusion and increasing liver volume. Case 2 A male child born by emergency caesarean section at 34 weeks’ gestation due to an abnormal fetal heart rhythm. At 33 weeks’ gestation, the prenatal ultrasound was declared normal. The baby, with an Apgar score of 1 and 2, was immediately intubated and transferred to the neonatal intensive care unit. Clinical examination revealed a distended bluish abdomen, collateral venous circulation, hepatomegaly and petechial purpura. Biological tests revealed bicytopenia, disseminated intravascular coagulation, liver failure and renal failure with oliguria. Ultrasound revealed a left adrenal mass displacing the left kidney and spleen, associated with heterogeneous hepatomegaly. Bone marrow aspiration revealed neuroblast infiltration. Due to the presence of life-threatening symptoms, carboplatin and etoposide-based chemotherapy was initiated on the first postnatal day. The first course of chemotherapy was complicated by severe tumor lysis syndrome accompanied by acute renal failure and a prolonged period of aplasia. Staphylococcus epidermidis and aureus septicemia complicated by septic shock occurred. Ultrasound showed stable hepatomegaly, but a slight decrease in the size of the adrenal mass. Due to multiple organ failure, the second course of chemotherapy was not administered. The child was declared dead at 64 days of age due to multi-organ failure resulting from sepsis leading to hypoxemia refractory to maximal therapy. Case 3 A male child born by emergency caesarean section at 33 weeks’ gestation following prenatal diagnosis of a spinal cord mass at L1, L2 and L3 extending into the right paravertebral portion of the spinal canal. Apgar scores were 2 and 10 at 5 and 10 minutes respectively. Neurological examination showed spontaneous movements of all four limbs with a vivid reflex of the lower limbs. Chemotherapy was initiated on the first postnatal day due to compression symptoms on imaging, with carboplatin and etoposide. Magnetic resonance imaging (MRI) after the first course showed clear regression of the tumor and ductal contingent. A second course of chemotherapy was administered. Grade 4 hematological toxicity was reported in both courses, as well as central line-associated bacteremia. Follow-up MRI after the second course showed a decrease in the small tissue infiltrate of the L1-L2 and T12-L1 foramen, and regression of the tumor and endocanal mass. Fifteen months later, the baby had normal neurological development, walked normally and showed no neurological symptoms. Case 4 A female child was born by scheduled caesarean section at 34 weeks’ gestation following a prenatal diagnosis of an intrathoracic paravertebral mass, raising suspicion of a dumbbell neuroblastoma. Apgar scores were 9 and 9 at 5 and 10 minutes respectively. Ultrasound examination showed a compressive thoracic intraspinal mass with extension through the vertebral foramina. Chemotherapy was started on the first postnatal day due to the presence of compressive symptoms, with vincristine in combination with cyclophosphamide. Despite this treatment, the compressive symptoms persisted, with an increase in the volume of the intraspinal component. A second and third course of carboplatin and etoposide-based chemotherapy were administered on postnatal days 15 and 30. MRI follow-up after the second treatment showed a marked decrease in the intrathoracic mass and intraspinal component. Metaiodobenzylguanidine (MIBG ) scintigraphy was performed and the SIOPEN score was 0. Three months after birth, surgical resection of the intrathoracic mass was performed. No further treatment was performed. This child had no major chemotherapy-related toxicities apart from profound aplasia after the second course of treatment and a feeding disorder that required parenteral nutrition. Nine months later, the baby showed no neurological symptoms, no deformation and normal bowel and bladder function. The final result was complete remission. Case 5 A male child born by emergency caesarean section at 33 weeks’ gestation due to an abnormal fetal heartbeat. The pregnancy had been marked by premature rupture of membranes at 31 weeks’ gestation, and the prenatal ultrasound had been deemed normal. The Apgar score was 0. He was immediately intubated and transferred to the neonatal intensive care unit. Clinical examination revealed a distended, bluish abdomen, collateral venous circulation and hepatomegaly. Biological tests revealed pancytopenia, hepatic and renal failure with oliguria. Ultrasound revealed a primary supra-renal mass with voluminous pseudomultinodulare hepatomegaly. Due to the presence of life-threatening symptoms, chemotherapy was initiated on postnatal day 1 with carboplatin and etoposide, complicated by grade 4 hepatotoxicity and prolonged febrile neutropenia. After stabilization of the tumor mass and resolution of life-threatening symptoms, two further courses of chemotherapy were administered. Ultrasound scans after the second course showed a reduction in the primary mass, and MIBG scintigraphy and skeletal X-rays were both negative. At one year and 10 months from the end of treatment, the child had a normal neurological examination and psychomotor development. Repeated ultrasound scans showed stable calcified liver lesions. Case 6 A male child born by scheduled caesarean section at 33 weeks’ gestation and 6 days after prenatal diagnosis of an adrenal mass associated with multi-nodular hepatomegaly, diagnosed by ultrasound and then confirmed by foetal MRI. Apgar score was 0, with no respiratory movement, requiring intubation and assisted ventilation. Clinical examination revealed tense hepatomegaly descending to the left hypochondrium. CT scan confirmed the presence of a retroperitoneal mass and a multi-nodular metastatic liver. There were no distant secondary localizations. The tumour was biopsied. Cytogenetic analysis by comparative genomic hybridization (CGH) array revealed an atypical segmental chromosomal aberration (SCA) with an 8q deletion and a 4q gain. Chemotherapy was initiated with two courses of etoposide and carboplatin. Ultrasound examination after the first course revealed regression of the tumour and hepatomegaly. Two additional cycles were administered. No haematological toxicity was reported. CT scan after the fourth session showed a moderate decrease in the volume of both adrenal masses, and overall stability of liver parenchyma heterogeneity. MIBG scintigraphy showed no abnormal uptake of the primary lesion in the left adrenal gland, possible fixation of the right adrenal gland, and homogeneous uptake of the liver parenchyma. Two additional courses of cyclophosphamide, doxorubicin and vincristine were administered. Re-evaluation showed a moderate decrease in the volume of both masses, stability of hepatic heterogeneity, Fluorodopa (FDOPA) Positron emission tomography (PET) revealed no focus of hypermetabolism, and no abnormal uptake on MIBG scintigraphy. Follow-up showed complete remission, and the child had normal development. Discussion Congenital tumors are very rare, with a reported incidence of 2 to 14 children per 100,000 live births, although there are probably many unreported cases (1). Among tumors encountered in the ante-natal period, neuroblastomas are the most frequent malignancies (2). The majority of neonatal neuroblastomas are managed using the “watch and wait” approach, due to their good vital prognosis, except in the case of hydrops fetalis, which occurs mainly when the disease is widely disseminated (3). However, in certain clinical situations where vital or functional risks are involved, urgent treatment with chemotherapy remains the standard of care. Neuroblastomas diagnosed prenatally are generally small and involve the adrenal gland (90%), while thoracic, retroperitoneal or cervical localizations have been exceptionally described (4). When measurements were regularly documented by ultrasound, tumor doubling time was found to be less than 15 days (4,5). Associated signs have been noted: hydramnios, fetal hydrops, hepatic metastases, fetal rhythm disorders, oligohydramnios, intrauterine growth retardation, acute fetal distress (6). In the event of in utero discovery of a highly probable neuroblastoma, the two main indications for induced preterm delivery are almost exclusively stage 4S neuroblastoma and dumbbell neuroblastoma with reduced movement of the lower limbs. A suprarenal mass associated with hepatomegaly is highly suggestive of the diagnosis of a particular form of metastatic neuroblastoma (stage 4S), which accounts for around 7-10% of all neuroblastoma cases (7). These patients have a small or undetectable primary tumor with metastases in one or more of the following sites: liver, skin, bone marrow, but not bone. A favorable outcome can be expected. However, the rapid spread of liver metastases can rapidly endanger the baby’s life through respiratory distress and liver failure. Numerous studies have shown that, in such cases, rapid initiation of intensive chemotherapy is necessary to push the neuroblastic cells towards regression (7). Several studies of full-term neonates have shown that survival is significantly correlated with age, with children under 2 months of age at diagnosis having a much poorer prognosis (8-10). Other key prognostic factors are amplification of the N-MYC oncogene (7-10), segmental chromosome alterations (11) and rapid progression of massive hepatomegaly (7,8). In cases of extremely rapid progression of liver metastases associated with severe clinical and/or biological signs, the first cyclophosphamide/vincristine regimen used, which was well tolerated but not very effective, was replaced by carboplatin or cisplatin/etoposide and cyclophosphamide/vincristine/doxorubicin combinations, with or without radiotherapy (8-10). Since this intensification of treatment, the proportion of children dying following chemotherapy is extremely low, and almost all deaths are due to life-threatening progression of liver tumours through respiratory distress and liver failure (7-10). The use of chemotherapy in premature infants is poorly understood and not codified. To our knowledge, there are no series reporting treatment of neuroblastoma with chemotherapy in premature infants, so we conducted this study to determine the tolerability and efficacy of these treatments in this very fragile population. Of the 6 infants in our series, 4 had 4S neuroblastoma with life-threatening symptoms. All received chemotherapy from the first day of life. It should be noted that the 2 deaths observed were due to very rapid tumor progression in children with the most severe clinical and biological symptoms, leading to death within 2 months. For one child (patient 1), the first course of chemotherapy consisted solely of etoposide due to impaired renal function, which may have been responsible for a poorer tumor response. However, combined carboplatin/etoposide treatment 21 days later was no more effective. Grade 4 hematological toxicity was observed in 3 of the 4 cases using chemotherapy doses recommended for full-term infants (carboplatin 6.6 mg/kg, etoposide 5 mg/kg for 3 days), complicated by sepsis in 2 cases. These four cases suggest that the hematological toxicity of the chemotherapy used was significant but manageable, but that despite its introduction on the first day of life, efficacy was only observed in 2 cases out of 4. The second therapeutic emergency is dumbbell neuroblastoma with symptoms of spinal cord compression. In these cases, the vital prognosis for the fetus is excellent, but premature delivery and prompt initiation of chemotherapy must be initiated to avoid permanent neurological deficits (12,13). In the very few published cases, chemotherapy was initiated at 36 weeks’ gestation at the earliest, and its tolerability has not been reported, with the exception of the case reported by Hawley et al. in which a 36-week premature infant was treated with carboplatin and etoposide (14). The particularity of this case is that carboplatin dose adaptation was used. After a total of 3 cycles, no hematological or other toxicities were observed and complete resolution of spinal cord compression was achieved. In one of our two cases, tumor progression was observed after the first treatment with vincristine and cyclophosphamide. However, in both cases, a clear reduction in tumour volume was observed after the first treatment with carboplatin and etoposide. No neurological sequelae were reported in our cases, as in the cases reported by Delahaye et al. and Walker et al. (15,16), but in contrast to the cases reported by Suffia et al. and Blackman et al. despite a good response to chemotherapy (17,18). To our knowledge, no case of radiotherapy in a premature newborn has been reported. The efficacy and toxicity of chemotherapy administered to term newborns have been relatively well known since the early 1990s. In the study by Michalowski et al, for example, among 14 babies treated with vincristine-cyclophosphamide and/or vincristine, cyclophosphamide and doxorubicin, no deaths were attributed to chemotherapy (19). Drugs whose neonatal use is relatively well documented (e.g. vincristine, doxorubicin, carboplatin, etoposide), and for which some pharmacokinetic data have been published, should be preferred (20). Chemotherapy in premature cancer patients is an extremely rare and complex scenario, requiring the consideration of several factors. These include immature hepatic enzyme systems and renal function, which affect drug metabolism and excretion, potentially leading to prolonged drug half-life and increased toxicity, as well as reduced hematopoietic reserves, making them highly susceptible to myelosuppression. There are no series on the toxicity and efficacy of chemotherapy in premature infants. The dosage of chemotherapy in this population is not established and is often extrapolated from that of full-term neonates and infants, with largely historical dose reductions based on extremely rare case reports (21,22). The challenges also faced by preterm neonates in the first few weeks of life are that their body water weight is greater than their body fat, making it difficult to dose chemotherapy correctly. Consequently, the rapid change in renal vascular resistance and renal blood flow, an important factor in drug clearance, the nephrogenesis that continues until 36 weeks’ gestation, the low GFR value of 0.6-0.8ml/min/1.73m², and the poor adaptation to the stressful catabolic state, add a significant challenge to overcome in the premature newborn. Although pharmacokinetic studies are very difficult to set up in situations of therapeutic urgency such as observed for certain stage 4S neuroblastomas and dumbbell tumors, they could be very useful, at least for drugs whose plasma concentration-time curve (AUC) has been shown to correlate closely with toxicity and efficacy (22). Conclusion In very rare cases of vital distress (stage 4S neuroblastoma) or functional distress (dumbbell neuroblastoma), chemotherapy must be instituted as a matter of urgency. Our series confirms the better efficacy of a treatment combining carboplatin and etoposide. However, the doses of these drugs are based only on empirical reductions from those prescribed for full-term infants, with the risk of being highly toxic and/or ineffective. The doses used in our series, close to those administered to full-term newborns, resulted in manageable hematological toxicity, but often associated with infections. The two deaths observed were linked to the rapid progression of stage 4S neuroblastomas and the lack of efficacy of the treatment. Pharmacokinetic studies, although difficult to perform in these emergency situations, should be carried out to obtain a better therapeutic index. Author contribution: - Andrew D.J. Pearson : Division of Clinical Studies, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, United Kingdom - Doz F : SIREDO Oncology Center of Care, Innovation and Research for Children, Adolescent and Young Adults with Cancer, Institut Curie, Paris, France Acknowledgments: All authors have contributed to the manuscript in significant ways, have reviewed and agreed upon the manuscript content References 1. Peiro JL, Sbragia L, Scorletti F, Lim FY. Perinatal Management of Fetal Tumors. Curr Pediatr Rev 2015;11:151-63. 2. Isaacs H. Fetal and neonatal neuroblastoma: retrospective review of 271 cases. Fetal Pediatr Pathol. 2007;26:177–84. 3. Campillo-Ajenjo M, PenaY-Burgos EM, HerrYero Ruiz B, Escuer Albero G, RubioY Aparicio P, Parrón Pajares SM, Bret Zurita M, Regojo-Zapata RT, Bartha Rasero JL, Alvarado EA. Congenital metastatic neuroblastoma with placental involvement as a rare cause of non-immune fetal hydrops. 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TABLE 1 Patients characteristics Sex Male Female 4 2 Patient age (gestation week) Between 28-32 weeks ≤ 37 weeks - 6 Birth weight 1500-2500 g ≥ 2500 g 4 2 Metastatic disease Yes No 4 2 Diagnostic in utero Yes No 3 3 Raised urinary catecholamines Yes No Unknown 4 1 1 TABLE 2 tumor characteristics 01 Adrenal gland Favourable Non amplified Unknown Elevated Yes 4S Elevated Elevated 02 Adrenal gland Unknown Non amplified Unknown Elevated No 4S Elevated Elevated 03 Paravertebral Unknown Non amplified Unknown Normal No L2 Not done Not done 04 Paravertebral Unknown Non amplified NCA Normal No L2 Not done Not done 05 Adrenal gland Unknown Unknown Unknown Elevated No 4S Elevated Elevated 06 Adrenal gland bilateral Unfavourable Non amplified SGA Elevated No 4S Not done Elevated NCA: numerical chromosome alteration SGA: segmental chromosome alteration TABLE 3 Treatment detail 01 At birth Day 1 post-natal 2400 Etoposide: 5 mg/kg day 1-3 1 Death Carboplatin: 6.6 mg/kg day 1-3 Etoposide: 5 mg/kg day 1-3 1 02 At birth Day 1 post-natal 2460 Carboplatin: 6.6 mg/kg day 1-3 Etoposide: 5 mg/kg day 1-3 1 Death 03 In utero Day 1 post-natal 2375 Carboplatin: 4.4 mg/kg day 1-3 Etoposide: 3.3 mg/kg day 1-3 2 Recovery 04 In utero Day 1 post-natal 2545 Vincristine 0.03 mg/kg day 1 Cyclophosphamide 3,3 mg/kg day 1-3 3 Recovery Carboplatin: 4.4 mg/kg day 1-2 than 2.5 mg/kg on day 3 Etoposide: 3.3 mg/kg day 1-3 2 05 At birth Day 1 post-natal 2225 Carboplatin: 6.6 mg/kg day 1-3 Etoposide: 5 mg/kg day 1-3 2 Recovery 06 In utero Day 1 post-natal 2200 Carboplatin: 6.6 mg/kg day 1-3 Etoposide: 5 mg/kg day 1-3 4 Recovery Vincristine 0.03 mg/kg day 1 and 5 Cyclophosphamide 3,3 mg/kg day 1-5 Doxorubicine 1 mg/kg day 4,5 2 Information & Authors Information Version history V1 Version 1 17 June 2025 Peer review timeline Published Pediatric Blood & Cancer Version of Record 24 Sep 2025 Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Pediatric Blood & Cancer Keywords chemotherapy molecular genetics neonatology neuroblastoma pharmacokinetics Authors Affiliations Dana AL KHALIFA [email protected] Universite de Lorraine College Lorrain des Ecoles Doctorales View all articles by this author Pascal Chastagner Universite de Lorraine College Lorrain des Ecoles Doctorales View all articles by this author Gudrun Schleiermacher 0000-0002-0133-5879 Institut Curie Departement d'Oncologie Medicale View all articles by this author Lejeune J Centre Hospitalier Regional Universitaire de Tours View all articles by this author Metrics & Citations Metrics Article Usage 379 views 241 downloads .FvxKWukQNSOunydq8rnd { width: 100px; } Citations Download citation Dana AL KHALIFA, Pascal Chastagner, Gudrun Schleiermacher, et al. Outcome of premature infants treated with chemotherapy for neuroblastoma in France.. Authorea . 17 June 2025. 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