Emerging therapies in Ewing sarcoma.

PURPOSE OF REVIEW: There is an unmet need to improve outcomes for patients for Ewing sarcoma, a rare, aggressive sarcoma with a peak incidence in adolescents and young adults (AYA). Current therapy at diagnosis involves multiagent chemotherapy and local therapy, but despite intensification of treatment, those with metastases at diagnosis and recurrent disease have poor outcomes. RECENT FINDINGS: Improved understanding of Ewing sarcoma biology has identified novel targets with promising activity in Ewing sarcoma patients, including tyrosine kinase inhibitors that are now undergoing evaluation as combination and maintenance therapy. Other emerging therapies include those that target the EWSR1::FLI1 fusion oncoprotein, and act on DNA damage, cell cycle and apoptotic pathways. Immunotherapeutic approaches, particularly CAR-T-cell therapy directed at GD2, also hold promise. Recent collaborative clinical trials that have defined an international standard of care for patients with newly diagnosed Ewing sarcoma and novel platform studies with adaptive designs offer unique opportunities to investigate these therapies inclusive of all ages. SUMMARY: Close international collaboration between clinicians and biologists will allow us to prioritize promising emerging therapies and develop biomarkers to facilitate their incorporation into standard of care and more rapidly translate into benefit for Ewing sarcoma patients.

Adolescent- and adult-onset neuroblastic tumor: A retrospective multicenter observational study of patients diagnosed in France between 2000 and 2020.

BACKGROUND: Adult- and adolescent-onset neuroblastomas are rare, with no established therapy. In addition, rare pheochromocytomas may harbor neuroblastic components. This study was designed to collect epidemiological, diagnostic and therapeutic data in order to better define the characteristics of malignant peripheral neuroblastic tumors (MPNT) and composite pheochromocytomas (CP) with MPNT. PROCEDURE: Fifty-nine adults and adolescents (aged over 15 years) diagnosed with a peripheral or composite neuroblastic tumor, who were treated in one of 17 institutions between 2000 and 2020, were retrospectively studied. RESULTS: Eighteen patients with neuroblastoma (NB) or ganglioneuroblastoma (GNB) had locoregional disease, and 28 patients had metastatic stage 4 NB. Among the 13 patients with CP, 12 had locoregional disease. Fifty-eight percent of the population were adolescents and young adults under 24 years of age. The probability of 5-year event-free survival (EFS) was 40% (confidence interval: 27%-53%). CONCLUSIONS: Outcomes were better for patients with localized tumor than for patients with metastases. For patients with localized tumor, in terms of survival, surgical treatment was the best therapeutic option. Multimodal treatment with chemotherapy, surgery, radiotherapy, and immunotherapy-based maintenance allowed long-term survival for some patients. Adolescent- and adult-onset neuroblastoma appeared to have specific characteristics associated with poorer outcomes compared to pediatric neuroblastoma. Nevertheless, complete disease control improved survival. The presence of a neuroblastic component in pheochromocytoma should be considered when making therapeutic management decisions. The development of specific tools/resources (Tumor Referral Board, Registry, biology, and trials with new agents or strategies) may help to improve outcomes for patients.

Metastatic adult-type non-rhabdomyosarcoma soft tissue sarcomas in children and adolescents: A cohort study from the European paediatric Soft tissue sarcoma Study Group.

BACKGROUND: Limited data exist on the clinical behavior of pediatric non-rhabdomyosarcoma soft tissue sarcomas (NRSTS) with distant metastases at onset, and a clear standard of care has not yet been defined. METHODS: This cohort study reports on pediatric adult-type metastatic NRSTS enrolled in two concurrent prospective European studies, i.e., the randomized BERNIE study and the single-arm MTS 2008 study developed by the European paediatric Soft tissue sarcoma Study Group. Treatment programs were originally designed for patients with metastatic rhabdomyosarcoma, i.e., nine courses of multidrug chemotherapy (with or without bevacizumab in the BERNIE study), followed by 12 cycles of maintenance therapy, whereas radiotherapy and/or surgery (on primary tumor and/or metastases) were delayed until after seven courses of chemotherapy had been administered. RESULTS: The study included 61 patients <21 years old treated from July 2008 to December 2016. The lung was the site of metastases in 75% of the cases. All patients received multi-agent chemotherapy, 44% had local therapy to primary tumor, and 18% had treatment of metastases. Median time to progression/relapse was 6 months. A high rate of tumor progression was observed during the initial part of the chemotherapy program. With a median follow-up of 41.5 months (range, 2-111 months), 3-year event-free survival and overall survival were 15.4% (95% confidence interval [CI], 7.6-25.7) and 34.9% (95% CI, 22.7-47.5), respectively. There were no statistically significant differences in outcome depending on the type of treatment administered. CONCLUSIONS: The study confirmed the overall poor outcome for patients with metastatic NRSTS, whose treatment remains a challenge. PLAIN LANGUAGE SUMMARY: Pediatric non-rhabdomyosarcoma soft tissue sarcomas form a heterogeneous group of rare tumors. Although recent international studies have defined the standard of care for patients with localized disease, limited data are available on the clinical behavior of patients with distant metastases. This study on 61 metastatic cases treated on two prospective European protocols confirms that the chances of survival of such patients are often dismal and a standard treatment is still lacking.

Malignant ectomesenchymoma in children: The European pediatric Soft tissue sarcoma Study Group experience.

Malignant ectomesenchymoma (MEM) is an extremely rare soft tissue tumor typical of young children, currently included in the category of skeletal muscle malignancies and characterized by a neuroblastic component. This study describes a series of 10 patients prospectively registered in the European paediatric Soft tissue sarcoma Study Group (EpSSG) database Of the 10 cases, seven had an initial local diagnosis of rhabdomyosarcoma. All patients received chemotherapy according to rhabdomyosarcoma strategy, four had radiotherapy. Overall, six patients were alive in first remission, two in second remission and one after second tumor. Only the patient with initially metastatic tumor died of disease.

Intra-abdominal desmoplastic small round cell tumor: The European pediatric Soft tissue sarcoma Study Group (EpSSG) experience.

BACKGROUND: This study describes the clinical findings of a consecutive series of pediatric and adolescent patients with a diagnosis of intra-abdominal desmoplastic small round cell tumor (DSRCT) prospectively enrolled in European pediatric Soft tissue sarcoma Study Group (EpSSG) protocols: the BERNIE study, the EpSSG MTS 2008 study, and the EpSSG NRSTS 2005 study. METHODS: Patients aged less than 21 years with a diagnosis of DSRCT arising in the abdomen were included. All trials recommended a multimodal approach including intensive multidrug chemotherapy and loco-regional treatment with surgery and/or radiotherapy whenever possible. RESULTS: The analysis included 32 cases (median age 13.7 years, male:female ratio 1.5:1). Three patients had localized tumors, seven had regionally disseminated disease, and 22 extraperitoneal metastases. All but one patient received multidrug chemotherapy and 11 had maintenance chemotherapy. Loco-regional treatment consisted of surgery only in seven cases, surgery plus adjuvant radiotherapy in 10, and radiotherapy only in six. Among the 17 cases who had radiotherapy, six had irradiation of the primary site, 10 had whole abdominopelvic radiotherapy plus boost to macroscopic residual disease, and one had irradiation to lung metastases only. With a median follow-up of 76 months (range: 18-124 months), 5-year event-free and overall survivals were 19.7% and 21.0%, respectively. Event-free survival was significantly worse for patients who did not receive loco-regional treatment (p-value .007). CONCLUSIONS: The study confirmed that the outcome of patients with DSRCT remains dismal and did not improve over recent years despite an intensive multimodal treatment approach.

Epithelioid hemangioendothelioma in children: The European Pediatric Soft Tissue Sarcoma Study Group experience.

The European pediatric Soft tissue sarcoma Study Group analyzed all children with epithelioid hemangioendothelioma prospectively registered in the NRSTS-05 (EUDRACT 2005-001139-31) and in MTS-2008 (NCT00379457) studies: 10 patients with localized and one with metastatic disease. Median age was 14.3 years (range, 9.0-18.8). Local therapy was initial primary surgery in seven cases, and five patients received systemic therapy. No patients received radiotherapy. After a median follow-up of 50 months (range, 6-176) for living patients, nine patients remain alive off therapy and two died. Five-year progression free and overall survivals are, respectively, 77.1% (95% confidence interval [CI]: 34.5-93.9) and 74.1% (95% CI: 28.1-93.0).

Pharmacogenetics in Neuroblastoma: What Can Already Be Clinically Implemented and What Is Coming Next?

Pharmacogenetics is one of the cornerstones of Personalized Precision Medicine that needs to be implemented in the routine of our patients' clinical management in order to tailor their therapies as much as possible, with the aim of maximizing efficacy and minimizing toxicity. This is of great importance, especially in pediatric cancer and even more in complex malignancies such as neuroblastoma, where the rates of therapeutic success are still below those of many other types of tumors. The studies are mainly focused on germline genetic variants and in the present review, state of the art is presented: which are the variants that have a level of evidence high enough to be implemented in the clinic, and how to distinguish them from the ones that still need validation to confirm their utility. Further aspects as relevant characteristics regarding ontogeny and future directions in the research will also be discussed.

MTHFR and VDR Polymorphisms Improve the Prognostic Value of MYCN Status on Overall Survival in Neuroblastoma Patients.

Single nucleotide polymorphisms (SNPs) in Pharmacogenetics can play an important role in the outcomes of the chemotherapy treatment in Neuroblastoma, helping doctors maximize efficacy and minimize toxicity. Employing AgenaBioscience MassArray, 96 SNPs were genotyped in 95 patients looking for associations of SNP with response to induction therapy (RIT) and grade 3-4 toxicities, in High Risk patients. Associations of SNPs with overall (OS) and event-free (EFS) survival in the whole cohort were also explored. Cox and logistic regression models with Elastic net penalty were employed. Association with grade 3-4 gastrointestinal and infectious toxicities was found for 8 different SNPs. Better RIT was correlated with rs726501 AG, rs3740066 GG, rs2010963 GG and rs1143684 TT (OR = 2.87, 1.79, 1.23, 1.14, respectively). EFS was affected by rs2032582, rs4880, rs3814058, rs45511401, rs1544410 and rs6539870. OS was influenced by rs 1801133, rs7186128 and rs1544410. Remarkably, rs1801133 in MTHFR (p = 0.02) and rs1544410 in VDR (p = 0.006) also added an important predictive value for OS to the MYCN status, with a more accurate substratification of the patients. Although validation studies in independent cohorts will be required, the data obtained supports the utility of Pharmacogenetics for predicting Neuroblastoma treatment outcomes.

Advances in emerging drugs for the treatment of neuroblastoma.

INTRODUCTION: Neuroblastoma is the most common solid extracranial tumor of childhood. Outcome for children with high-risk neuroblastoma remains suboptimal. More than half of children diagnosed with high-risk neuroblastoma either do not respond to conventional therapies or relapse after treatment with dismal prognosis. Areas covered: This paper presents a short review of the state of the art in the current treatment of high-risk neuroblastoma. An updated review of new targeted therapies in this group of patients is also presented. Expert opinion: In order to improve prognosis for high-risk patients there is an urgent need to better understand spatial and temporal heterogeneity and obtain new predictive preclinical models in neuroblastoma. Combination strategies with conventional chemotherapy and/or other targeted therapies may overcome current ALK inhibitors resistance. Improvement of international and transatlantic cooperation to speed clinical trials accrual is needed.

Postrelapse Prognostic Factors in Nonmetastatic Osteosarcoma: A Single-institution Experience.

PURPOSE: The purpose of this study was to analyze the prognostic factors that influence postrelapse survival (PRS) in children and adolescents with initial localized high-grade osteosarcoma. METHODS/PATIENTS: This is a retrospective evaluation of patients aged 21 years and below with nonmetastatic high-grade osteosarcoma treated at our institution from 1985 to 2011 who developed recurrent disease after achievement of an initial complete response (CR). PRS and postrelapse event-free survival (PREFS) analyses were performed using the Kaplan-Meier method and log-rank test. Multivariate Cox regression analysis was used to determine which variables were independently prognostic. RESULTS: Thirty-one patients were included. Median age at primary diagnosis was 13.7 years (range, 1.9 to 21.0 y). Median time to first relapse was 16 months (range, 3 to 36 mo). Fourteen patients achieved a second CR (CR2) after surgery±chemotherapy treatment. The 5-year PRS and PREFS were both 26% (95% confidence interval, 14%-49%), with a median follow-up of 99 months (range, 27 to 271 mo). Multivariate analysis showed that achievement of CR2 (P<0.001) and histologic response to first-line treatment (P=0.02) were significantly associated with PRS, whereas time to first relapse did not retain univariate significance. CONCLUSIONS: Achievement of CR2 and histologic response to preoperative first-line treatment are independent survival prognostic factors in osteosarcoma recurrence.

Presentation and Long-term Outcome of High-grade Osteosarcoma: A Single-institution Experience.

PURPOSE: To evaluate clinicopathologic characteristics, prognostic factors, and treatment outcome of pediatric/adolescent high-grade osteosarcoma patients. METHODS/PATIENTS: Retrospective evaluation of patients 21 years of age or younger with newly diagnosed high-grade osteosarcoma treated in a single institution. Effects of variables on event-free survival and overall survival (OS) were determined by using Kaplan-Meier survival analysis. Variables found to be significant were evaluated with multivariable Cox regression analysis. RESULTS: Seventy-seven patients diagnosed between January 1985 and December 2011 were included. Median follow-up time was 11.0 years (range, 1.6 to 26.4 y). Event-free survival at 5 and 10 years was 38%±11% and 38%±11%, respectively. OS at 5 and 10 years was 51%±12% and 45%±12%, respectively. Metastatic disease, prolonged time interval to resumption of chemotherapy, lower tumor necrosis rate, and lack of achievement of complete response at the end of first-line chemotherapy treatment were associated with inferior OS probabilities in univariate analysis. Upon multivariate analysis, only achievement of complete response at the end of first-line chemotherapy and tumor necrosis rate retained independent prognostic significance. CONCLUSIONS: Prognostic factors and long-term survival are similar to those previously described. Reduction of global time interval to resumption of chemotherapy as well as a more specific and validated definition of pulmonary metastases at diagnosis are needed.

Multimodality Treatment of Pediatric and Adult Patients With Ewing Sarcoma: A Single-institution Experience.

INTRODUCTION: The treatment of Ewing Sarcoma family of tumors is multimodal, both in children and adults. Axial location and metastases are classic prognostic factors. However, the worse prognosis in older patients is more controversial. METHODS: Retrospective analysis was performed of pediatric and adult patients treated with the 2001 SEOP protocol: 6 cycles of VIDE chemotherapy (CT). If no progression was observed, local (surgery and/or radiotherapy) and consolidation treatments were performed adjusted to prognosis: 8 cycles of VAC in standard-risk patients or 1 cycle of VAC and high-dose CT and autologous transplant in the case of increased risk.We analyzed induction CT toxicity, type of consolidation treatment, and disease-free (DFS) and overall (OS) survival by the Kaplan-Meier method, with a log-rank analysis of prognostic factors with regard to OS. RESULTS: Thirty-six patients were analyzed (2003 to 2011). Sixty percent were male, with a median age of 16 years (range, 7 to 57 y). The most frequent location was axial (43%), followed by extremities (34%), extraosseous (18%), and ribs (9%). Fifty-four percent of patients had metastases, of which, 58% were pulmonary.The median follow-up period was 36 months (5 to 101 mo). Median DFS was 25 months (16 to 34 mo) and median OS 29 months (19 to 40 mo), with a 3-year OS of 40%. Median OS from progression was 7 months (0.4 to 15 mo). Age <15 years and normal lactate dehydrogenase levels were associated with prolonged OS. CONCLUSIONS: Induction CT with the VIDE regimen was feasible in most patients, with a low risk for early progression. Hematological toxicity was substantial but manageable. Adult patients had a worse prognosis. Survival after progression was dismal.

From biology to personalized medicine: Recent knowledge in osteosarcoma.

High-grade osteosarcoma is the most common paediatric bone cancer. More than one third of patients relapse and die of osteosarcoma using current chemotherapeutic and surgical strategies. To improve outcomes in osteosarcoma, two crucial challenges need to be tackled: 1-the identification of hard-to-treat disease, ideally from diagnosis; 2- choosing the best combined or novel therapies to eradicate tumor cells which are resistant to current therapies leading to disease dissemination and metastasize as well as their favorable microenvironment. Genetic chaos, tumor complexity and heterogeneity render this task difficult. The development of new technologies like next generation sequencing has led to an improvement in osteosarcoma oncogenesis knownledge. This review summarizes recent biological and therapeutical advances in osteosarcoma, as well as the challenges that must be overcome in order to develop personalized medicine and new therapeutic strategies and ultimately improve patient survival.

Clinical trial inclusion in patients with relapsed/refractory neuroblastoma following the European Precision Cancer Medicine trial MAPPYACTS.

INTRODUCTION: Despite poor survival for patients with relapsed or refractory neuroblastoma, only 10-16% of patients are reported to be included in early phase trials. This study aimed to explore the impact of molecular profiling within the prospective precision cancer medicine trial MAPPYACTS (NCT02613962) on subsequent early phase trial recruitment and treatment by matched targeted therapies in this population. METHODS AND MATERIALS: Clinical data from all French patients with relapsed/refractory neuroblastoma enrolled in MAPPYACTS were analyzed for subsequent matched/non-matched targeted treatment based on clinical tumor board (CMTB) recommendations. RESULTS: From 93 patients with neuroblastoma included in French centers, 78 (84%) underwent whole exome and RNA sequencing and were discussed in the CMTB. Higher rate of successful sequencing analysis was observed in patients with relapsed disease compared to those with refractory disease (p = 0.0002). Among the 50 patients that presented with a new disease relapse/progression after the CMTB recommendations, 35 patients (70%) had at least one actionable alteration identified on the tumor at the time of relapse. Eighteen patients (36%) were included in an early phase clinical trial, 11 of these with a matched agent, 7 with a non-matched treatment; 13 patients were included in the AcSé ESMART trial. Five patients (10%) received a matched targeted therapy outside a clinical trial. CONCLUSION: Patients with neuroblastoma in the European MAPPYACTS trial were more likely to be included in early phase trials compared to previous reports. Early deep sequencing at first treatment failure, comprehensive therapeutic discussions in molecular tumor boards and innovative trials like AcSé -ESMART improve access to innovative therapies for patients with relapsed/refractory neuroblastoma. CLINICAL TRIAL REGISTRATION: NCT02613962.

Imaging characterization of paediatric tumours with the neurotrophic tyrosine receptor kinase fusion transcript.

OBJECTIVES: The neurotrophic tyrosine receptor kinase (NTRK) fusion transcript (FT) is a major genetic landmark of infantile fibrosarcoma (IFS) and cellular congenital mesoblastic nephroma (cCMN) but is also described in other tumours. The recent availability of NTRK-targeted drugs enhances the need for better identification. We aimed to describe the anatomic locations and imaging features of tumours with NTRK-FT in children. CASE SERIES: Imaging characteristics of NTRK-FT tumours of 41 children (median age: 4 months; 63% <1 year old; range: 0-188) managed between 2001 and 2019 were retrospectively analysed. The tumours were located in the soft tissues (n = 24, including 19 IFS), kidneys (n = 9, including 8 cCMN), central nervous system (CNS) (n = 5), lung (n = 2), and bone (n = 1). The tumours were frequently deep-located (93%) and heterogeneous (71%) with necrotic (53%) or haemorrhagic components (29%). Although inconstant, enlarged intratumoural vessels were a recurrent finding (70%) with an irregular distribution (63%) in the most frequent anatomical locations. CONCLUSION: Paediatric NTRK-FT tumours mainly occur in infants with very variable histotypes and locations. Rich and irregular intra-tumoural vascularization are recurrent findings. ADVANCES IN KNOWLEDGE: Apart from IFS of soft tissues and cCMN of the kidneys, others NTRK-FT tumours locations have to be known, as CNS tumours. Better knowledge of the imaging characteristics may help guide the pathological and biological identification.

Chemo-immunotherapy with dinutuximab beta in patients with relapsed/progressive high-risk neuroblastoma: does chemotherapy backbone matter?

BACKGROUND: Addition of anti-GD2 antibodies to temozolomide-based chemotherapy has demonstrated increased antitumor activity and progression-free survival in patients with relapsed/progressive high-risk neuroblastoma. However, chemo-immunotherapy is not yet approved for this indication. This study presents the chemo-immunotherapy experience in patients with relapsed/progressive high-risk neuroblastoma treated within the off-label use program of the Neuroblastoma Committee of the French Society of Pediatric Oncology (SFCE). METHODS: Dinutuximab beta (dB) was administered alongside temozolomide-topotecan (TOTEM) or temozolomide-irinotecan (TEMIRI) at first disease relapse/progression or topotecan-cyclophosphamide (TopoCyclo) at further relapse/progression. Real-world data on demographics, treatment, antitumor activity and safety was collected from all patients after inclusion in SACHA-France (NCT04477681), a prospective national registry, which documents safety and efficacy data on innovative anticancer therapies prescribed to patients ≤ 25 years old as compassionate or off-label use. RESULTS: Between February 2021 and July 2023, 39 patients with confirmed relapsed/progressive high-risk neuroblastoma (median age 6 years, range 1-24) were treated with dB+TopoCyclo (n = 24) or dB+TOTEM/TEMIRI (n = 15) across 17 centers. In total, 163 chemo-immunotherapy cycles were administered, main toxicities were mild or moderate, with higher incidence of hematological adverse drug reactions with dB+TopoCyclo than dB+TOTEM/TEMIRI. Objective response rate was 42% for dB+TopoCyclo (CI95% 22-63%) and 40% for dB+TOTEM/TEMIRI (CI95% 16-68%). CONCLUSION: Similar objective response rates for dB+TopoCyclo and dB+TOTEM/TEMIRI in patients with relapsed/progressive high-risk neuroblastoma emphasize the importance of chemo-immunotherapy, irrespective of the chemotherapy backbone.

Sequential analysis of cfDNA reveals clonal evolution in neuroblastoma patients receiving ALK targeted therapy.

PURPOSE: The study of cell free DNA (cfDNA) enables sequential analysis of tumor cell-specific genetic alterations in neuroblastoma patients. EXPERIMENTAL DESIGN: Eighteen patients with relapsing neuroblastoma having received Lorlatinib, a 3rd generation ALK inhibitor, were identified (SACHA national registry and/or in the institution). cfDNA was analyzed at relapse for 9 patients, and sequentially for 5 patients (blood/bone marrow plasma) by performing WGS library construction followed by ALK-targeted ddPCR of the hotspot mutations (F1174L, R1275Q, I1170N) (variant allele fraction (VAF) detection limit 0.1%) and WES to evaluate disease burden and clonal evolution, following comparison with tumor/germline WES. RESULTS: Overall response rate to Lorlatinib was 33% (CI 13-59%), with response observed in 6/10 cases without versus 0/8 cases with MYCN amplification (MNA). ALK VAFs correlated with the overall clinical disease status, with a VAF<0.1% in clinical remission, versus higher VAFs (>30%) at progression. Importantly, sequential ALK ddPCR detected relapse earlier than clinical imaging. cfDNA WES revealed new SNVs, not seen in the primary tumor, in all instances of disease progression after Lorlatinib treatment, indicating clonal evolution, including alterations in genes linked to tumor aggressivity (TP53) or novel targets (EGFR). Gene pathway analysis revealed an enrichment for genes targeting cell differentiation in emerging clones, and cell adhesion in persistent clones. Evidence of clonal hematopoiesis could be observed in follow-up samples. CONCLUSION: We demonstrate the clinical utility of combining ALK cfDNA ddPCR for disease monitoring and cfDNA WES for the study of clonal evolution and resistance mechanisms in neuroblastoma patients receiving ALK targeted therapy.

Emerging drugs for neuroblastoma.

INTRODUCTION: Neuroblastoma accounts for 8 - 10% of pediatric cancers and is responsible for 15% of childhood cancer deaths. Despite multimodality treatment, the overall survival (OS) and event-free survival (EFS) in high-risk patients remain suboptimal. More than half of children diagnosed with high-risk neuroblastoma either do not respond to conventional therapies or relapse after treatment. AREAS COVERED: This review discusses about the unmet medical needs for new therapeutic options against high-risk neuroblastoma. New drugs and therapeutic strategies that are under development in clinical trials, which are currently recruiting patients. EXPERT OPINION: There is a need to improve the response rate of induction chemotherapy, which is not effective in a third of patients and also the other components of the current treatment, little efficacious in avoiding the relapses. Few drugs have been introduced as upfront therapy in the last years. Topotecan, irinotecan and temozolomide are expected to improve the response in high-risk neuroblastoma, but their impact on OS and EFS is unknown. Anti-GD2 antibodies combined with other immunomodulators (IL-2, GM-CSF) are an important advance in the treatment of these children. Nevertheless, the hope is put in the new drugs directed to molecular targets of neuroblastoma. Anti-angiogenic drugs, ALK antagonist and PI3K/Akt/mTOR inhibitors are among the most promising.

Oral vinorelbine in young patients with desmoid-type fibromatosis.

BACKGROUND: Desmoid-type fibromatosis are rare intermediate tumors in children and adolescents. Owing to local aggressiveness and relapse, systemic treatment for symptomatic advanced or progressive forms is recommended. Following promising results in adult patients, oral vinorelbine is investigated in young patients. METHODS: A retrospective review of young patients (<25 years old) with advanced or progressive desmoid type fibromatosis treated with oral vinorelbine in eight large centers of the Société Française des Cancers de l'Enfant was performed. In addition to tumor assessment according to RECIST 1.1, pre-treatment and during-treatment imagery were reviewed centrally to assess tumor volume and estimate fibrosis score through the change in percentage in hypoT2 signal intensity. RESULTS: From 2005 to 2020, 24 patients (median age 13.9 years [range, 1.0-23.0]) received oral vinorelbine. Median number of prior systemic lines of treatment was 1 (range, 0-2), mainly based on intravenous low dose methotrexate and vinblastine. Before vinorelbine initiation, all patients had a progressive disease: radiological for 19, radiological and clinical (pain) for three and only clinical for two. Oral vinorelbine was delivered for a median duration of 12 months (range, 1-42). The toxicity profile was favorable, with no grade 3-4 event. Overall response estimated on 23 evaluable patients according to RECIST 1.1 criteria was three partial responses (13%), 18 stabilization (78%) and two progressive disease (9%). Overall progression-free survival was 89.3% (95% confidential intervals 75.2-100) at 24 months. Four stable tumors according to standard RECIST criteria displayed a partial response with > 65% tumor volume reduction. Among 21 informative patients, the estimated fibrosis score decreased for 15 patients, was stable for four patients and increased for two patients. CONCLUSION: Oral vinorelbine seems to be effective to control advanced or progressive desmoid type fibromatosis in young patients, with a well-tolerated profile. These results support testing this drug as first-line alone or in combination to improve response rate while preserving quality of life.