Background
Risk stratification is crucial to treatment decision‐making in neuroblastoma. This study aimed to explore factors present at diagnosis affecting outcome in patients aged ≥18 months with ...metastatic neuroblastoma and to develop a simple risk score for prognostication.
Procedure
Data were derived from the European high‐risk neuroblastoma 1 (HR‐NBL1)/International Society for Paediatric Oncology European Neuroblastoma (SIOPEN) trial with analysis restricted to patients aged ≥18 months with metastatic disease and treated prior to the introduction of immunotherapy. Primary endpoint was 5‐year event‐free survival (EFS). Prognostic factors assessed were sex, age, tumour MYCN amplification (MNA) status, serum lactate dehydrogenase (LDH)/ferritin, primary tumour and metastatic sites. Factors significant in univariate analysis were incorporated into a multi‐variable model and an additive scoring system developed based on estimated log‐cumulative hazard ratios.
Results
The cohort included 1053 patients with median follow‐up 5.5 years and EFS 27 ± 1%. In univariate analyses, age; serum LDH and ferritin; involvement of bone marrow, bone, liver or lung; and >1 metastatic system/compartment were associated with worse EFS. Tumour MNA was not associated with worse EFS. A multi‐variable model and risk score incorporating age (>5 years, 2 points), serum LDH (>1250 U/L, 1 point) and number of metastatic systems (>1, 2 points) were developed. EFS was significantly correlated with risk score: EFS 52 ± 9% for score = 0 versus 6 ± 3% for score = 5 (P < 0.0001).
Conclusions
A simple score can identify an “ultra‐high risk” (UHR) cohort (score = 5) comprising 8% of patients with 5‐year EFS <10%. These patients appear not to benefit from induction therapy and could potentially be directed earlier to alternative experimental therapies in future trials.
Background:
Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor that is used off-label for select cases of recurrent respiratory papillomatosis (RRP) that are severe, involve the ...distal airway or lung parenchyma, and refractory to other forms of adjuvant therapy. However, there is limited safety data for the use of bevacizumab in children and VEGF inhibitors are reported to have a range of adverse renal effects, including hypertension, proteinuria, and thrombotic microangiopathy (TMA).
Case-Diagnosis/Treatment:
This report describes a case of severe juvenile-onset RRP that had an exceptionally high operative burden that was refractory to several adjuvant treatment strategies (including intralesional cidofovir and subcutaneous pegylated interferon). Bevacizumab treatment resulted in a dramatic and sustained improvement in disease control over a 5-year period. However, after 3 years of treatment, the patient developed hypertension and proteinuria and was found to have evidence of a glomerular TMA on kidney biopsy. These complications were successfully managed with a reduction in bevacizumab frequency and angiotensin-converting enzyme inhibitor initiation.
Conclusions:
Clinicians caring for children treated with VEGF inhibitors should be aware of the potential renal complications and their management.
Given the biological and clinical heterogeneity of neuroblastoma, risk stratification is vital to determining appropriate treatment. Historically, most patients with high‐risk neuroblastoma (HR‐NBL) ...have been treated uniformly without further stratification. Attempts have been made to identify factors that can be used to risk stratify these patients and to characterize an “ultra‐high‐risk” (UHR) subpopulation with particularly poor outcome. However, among published data, there is a lack of consensus in the definition of the UHR population and heterogeneity in the endpoints and statistical methods used. This review summarizes our current understanding of stratification of HR‐NBL and discusses the complex issues in defining UHR neuroblastoma.
The Role of Surgery in High-risk Neuroblastoma Ryan, Anne L; Akinkuotu, Adesola; Pierro, Agostino ...
Journal of pediatric hematology/oncology,
01/2020, Letnik:
42, Številka:
1
Journal Article
Recenzirano
Although intensive multimodal treatment has improved outcomes for patients with high-risk neuroblastoma, the specific role of primary tumor resection remains controversial. Many studies have been ...designed to determine whether the extent of surgical resection impacts survival; however, these reports have demonstrated conflicting results. There is also ongoing debate regarding the timing of primary tumor resection, with subtle differences in the approach between the large pediatric oncology cooperative consortia. Most of the published literature to date has been approached from a surgical viewpoint. Although most evidence supports surgery as part of the local control approach for high-risk neuroblastoma, recommendations for timing and extent of surgical resection are not consistent. This review summarizes our current understanding from the perspectives of both the pediatric oncologist and pediatric surgeons and discusses how the objectives of neuroblastoma primary surgical resection are different from that of other malignancies. Furthermore, this commentary will address how retrospective surgical outcome data may be interpreted in the setting of modern era high-risk neuroblastoma treatment.
Activated human blood γδ T cells have also been previously demonstrated to behave as professional APCs, although the processes that control APC function have not been characterized. n this study, we ...show that the acquisition of potent APC function by human blood γδ T cells is achieved after physical interaction with an Ab-coated target cell, a process that we refer to as licensing. In cancer models, licensing of γδ T cells by tumor-reactive mAbs promotes the uptake of tumor Ags and professional presentation to tumor-reactive αβ T cells. We propose that licensing by Ab is a mechanism whereby the adaptive properties of γδ T cells are induced by their innate functions in a spatially and temporally controlled manner.
Activated human blood gamma delta T cells have also been previously demonstrated to behave as professional APCs, although the processes that control APC function have not been characterized. n this ...study, we show that the acquisition of potent APC function by human blood gamma delta T cells is achieved after physical interaction with an Ab-coated target cell, a process that we refer to as licensing. In cancer models, licensing of gamma delta T cells by tumor-reactive mAbs promotes the uptake of tumor Ags and professional presentation to tumor-reactive alpha beta T cells. We propose that licensing by Ab is a mechanism whereby the adaptive properties of gamma delta T cells are induced by their innate functions in a spatially and temporally controlled manner.
Neurotrophic tyrosine receptor kinase gene fusions (
) are oncogenic drivers present at a low frequency in most tumour types (<5%), and at a higher frequency (>80%) in a small number of rare tumours ...(e.g., infantile fibrosarcoma IFS) and considered mutually exclusive with other common oncogenic drivers. Health Canada recently approved two tyrosine receptor kinase (TRK) inhibitors, larotrectinib (for adults and children) and entrectinib (for adults), for the treatment of solid tumours harbouring
gene fusions. In Phase I/II trials, these TRK inhibitors have demonstrated promising overall response rates and tolerability in patients with TRK fusion cancer who have exhausted other treatment options. In these studies, children appear to have similar responses and tolerability to adults. In this report, we provide a Canadian consensus on when and how to test for
gene fusions and when to consider treatment with a TRK inhibitor for pediatric patients with solid tumours. We focus on three pediatric tumour types: non-rhabdomyosarcoma soft tissue sarcoma/unspecified spindle cell tumours including IFS, differentiated thyroid carcinoma, and glioma. We also propose a tumour-agnostic consensus based on the probability of the tumour harbouring an
gene fusion. For children with locally advanced or metastatic TRK fusion cancer who have either failed upfront therapy or lack satisfactory treatment options, TRK inhibitor therapy should be considered.
More than half of the patients with high-risk neuroblastoma (NB) will relapse despite intensive multimodal therapy, with an additional 10% to 20% refractory to induction chemotherapy. Management of ...these patients is challenging, given disease heterogeneity, resistance, and organ toxicity including poor hematological reserve. This review will discuss the current treatment options and consider novel therapies on the horizon. Cytotoxic chemotherapy regimens for relapse and refractory NB typically center on the use of the camptothecins, topotecan and irinotecan, in combination with agents such as cyclophosphamide and temozolomide, with objective responses but poor long-term survival. I-meta-iodobenzylguanidine therapy is also effective for relapsed patients with meta-iodobenzylguanidine-avid disease, with objective responses in a third of cases. Immunotherapy with anti-GD2 has recently been incorporated into upfront therapy, but its role in the relapse setting remains uncertain, especially for patients with bulky disease. Future cell-based immunotherapies and other approaches may be able to overcome this limitation. Finally, many novel molecularly targeted agents are in development, some of which show specific promise for NB. Successful incorporation of these agents will require combinations with conventional cytotoxic chemotherapies, as well as the development of predictive biomarkers, to ultimately personalize approaches to patients with "targetable" molecular abnormalities.
Checkpoint inhibitors have limited efficacy for children with unselected solid and brain tumors. We report the first prospective pediatric trial (NCT02992964) using nivolumab exclusively for ...refractory nonhematologic cancers harboring tumor mutation burden (TMB) ≥5 mutations/megabase (mut/Mb) and/or mismatch repair deficiency (MMRD).
Twenty patients were screened, and 10 were ultimately included in the response cohort of whom nine had TMB >10 mut/Mb (three initially eligible based on MMRD) and one patient had TMB between 5 and 10 mut/Mb.
Delayed immune responses contributed to best overall response of 50%, improving on initial objective responses (20%) and leading to 2-year overall survival (OS) of 50% 95% confidence interval (CI), 27-93. Four children, including three with refractory malignant gliomas are in complete remission at a median follow-up of 37 months (range, 32.4-60), culminating in 2-year OS of 43% (95% CI, 18.2-100). Biomarker analyses confirmed benefit in children with germline MMRD, microsatellite instability, higher activated and lower regulatory circulating T cells. Stochastic mutation accumulation driven by underlying germline MMRD impacted the tumor microenvironment, contributing to delayed responses. No benefit was observed in the single patient with an MMR-proficient tumor and TMB 7.4 mut/Mb.
Nivolumab resulted in durable responses and prolonged survival for the first time in a pediatric trial of refractory hypermutated cancers including malignant gliomas. Novel biomarkers identified here need to be translated rapidly to clinical care to identify children who can benefit from checkpoint inhibitors, including upfront management of cancer. See related commentary by Mardis, p. 4701.
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