Stephen S. Roberts

Ifosfamide, carboplatin, and etoposide for neuroblastoma: a high-dose salvage regimen and review of the literature.

The authors report a retrospective analysis of high‐dose ifosfamide, carboplatin, and etoposide (HD‐ICE) for patients with refractory or relapsed neuroblastoma (NB). A major reason for using this regimen was the long time since patients received previous treatment with a platinum compound. The authors also summarized the published experience on ICE in patients with NB.

Lack of survival advantage with autologous stem-cell transplantation in high-risk neuroblastoma consolidated by anti-G D2 immunotherapy and isotretinoin

Since 2003, high-risk neuroblastoma (HR-NB) patients at our center received anti-GD2 antibody 3F8/GM-CSF + isotretinoin – but not myeloablative therapy with autologous stem-cell transplantation (ASCT). Post-ASCT patients referred from elsewhere also received 3F8/GM-CSF + isotretinoin. We therefore accrued a study population of two groups treated during the same period and whose consolidative therapy, aside from ASCT, was identical. We analyzed patients enrolled in 1st complete/very good partial remission (CR/VGPR). Their event-free survival (EFS) and overall survival (OS) were calculated from study entry. Large study size allowed robust statistical analyses of key prognosticators including MYCN amplification, minimal residual disease (MRD), FCGR2A polymorphisms, and killer immunoglobulin-like receptor genotypes of natural killer cells. The 170 study patients included 60 enrolled following ASCT and 110 following conventional chemotherapy. The two cohorts had similar clinical and biological features. Five-year rates for ASCT and non-ASCT patients were, respectively: EFS 65% vs. 51% (p = .128), and OS 76% vs. 75% (p = .975). In multivariate analysis, ASCT was not prognostic and only MRD-negativity after two cycles of 3F8/GM-CSF correlated with significantly improved EFS and OS. Although a trend towards better EFS is seen with ASCT, OS is near identical. Cure rates may be similar, as close surveillance detects localized relapse and effective salvage treatments are applied. ASCT may not be needed to improve outcome when anti-GD2 immunotherapy is used for consolidation after dose-intensive conventional chemotherapy.

Immunotherapy of Childhood Sarcomas

Pediatric sarcomas are a heterogeneous group of malignant tumors of bone and soft tissue origin. Although more than 100 different histologic subtypes have been described, the majority of pediatric cases belong to the Ewing’s family of tumors, rhabdomyosarcoma and osteosarcoma. Most patients that present with localized stage are curable with surgery and/or chemotherapy; however, those with metastatic disease at diagnosis or those who experience a relapse continue to have a very poor prognosis. New therapies for these patients are urgently needed. Immunotherapy is an established treatment modality for both liquid and solid tumors, and in pediatrics, most notably for neuroblastoma and osteosarcoma. In the past, immunomodulatory agents such as interferon, interleukin-2, and liposomal-muramyl tripeptide phosphatidyl-ethanolamine have been tried, with some activity seen in subsets of patients; additionally, various cancer vaccines have been studied with possible benefit. Monoclonal antibody therapies against tumor antigens such as disialoganglioside GD2 or immune checkpoint targets such as CTLA-4 and PD-1 are being actively explored in pediatric sarcomas. Building on the success of adoptive T cell therapy for EBV-related lymphoma, strategies to redirect T cells using chimeric antigen receptors and bispecific antibodies are rapidly evolving with potential for the treatment of sarcomas. This review will focus on recent preclinical and clinical developments in targeted agents for pediatric sarcomas with emphasis on the immunobiology of immune checkpoints, immunoediting, tumor microenvironment, antibody engineering, cell engineering, and tumor vaccines. The future integration of antibody-based and cell-based therapies into an overall treatment strategy of sarcoma will be discussed.

Integrating Genomics Into Clinical Pediatric Oncology Using the Molecular Tumor Board at the Memorial Sloan Kettering Cancer Center

Pediatric oncologists have begun to leverage tumor genetic profiling to match patients with targeted therapies. At the Memorial Sloan Kettering Cancer Center (MSKCC), we developed the Pediatric Molecular Tumor Board (PMTB) to track, integrate, and interpret clinical genomic profiling and potential targeted therapeutic recommendations.

STRIKING DICHOTOMY IN OUTCOME OF MYCN-AMPLIFIED NEUROBLASTOMA IN THE CONTEMPORARY ERA

The authors exploited a large database to investigate the outcomes of patients with high‐risk neuroblastoma in the contemporary era.

Posterior reversible encephalopathy syndrome in neuroblastoma patients receiving anti-GD2 3F8 monoclonal antibody.

Posterior reversible encephalopathy syndrome (PRES) comprises clinical and radiologic findings with rapid onset and potentially dire consequences. Patients experience hypertension, seizures, headache, visual disturbance, and/or altered mentation. Magnetic resonance imaging reveals edematous changes in the brain (especially in the parietal and occipital lobes). In this report, the authors describe PRES associated with antidisialoganglioside (anti‐GD2) monoclonal antibody (MoAb) immunotherapy, which is now standard for high‐risk neuroblastoma but has not previously been implicated in PRES.

A phase I/Ib trial targeting the Pi3k/Akt pathway using perifosine: Long-term progression-free survival of patients with resistant neuroblastoma

AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high‐risk neuroblastoma (HR‐NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR‐NB experience. HR‐NB patients received perifosine 50–75 mg m−2 day−1 after a loading dose of 100–200 mg m−2 on day 1, and continued on study until progressive disease. The 27 HR‐NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1–5 (median 2) relapses; only one had MYCN‐amplified HR‐NB. Pharmacokinetic studies showed μM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN‐non‐amplified) remained progression‐free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal 123I‐metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11–62 months, median 38) in the nine long‐term progression‐free survivors. The clinical findings (i) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; (ii) support perifosine for MYCN‐non‐amplified HR‐NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and (iii) highlight the welcome possibility that refractory or relapsed MYCN‐non‐amplified HR‐NB is potentially curable.

Combination of bevacizumab, irinotecan, and temozolomide for refractory or relapsed neuroblastoma: Results of a phase II study

The rationale for studying the combination of bevacizumab, irinotecan, and temozolomide (BIT) in neuroblastoma (NB) is based on the following: (i) vascular endothelial growth factor (VEGF) expression is associated with an aggressive phenotype, (ii) anti‐VEGF antibody bevacizumab enhances irinotecan‐mediated suppression of NB xenografts, (iii) bevacizumab safety has been established in pediatric phase I studies, and (iv) irinotecan + temozolomide (IT) is a standard salvage chemotherapy.

Osteochondroma in Long-Term Survivors of High-Risk Neuroblastoma

Osteochondromas are benign bony protrusions that can be spontaneous or associated with radiotherapy (RT). Current treatment of high‐risk neuroblastoma includes dose‐intensive chemotherapy, local RT, an anti‐GD2 monoclonal antibody (MoAb), and isotretinoin. Late effects are emerging.

When Overall Survival Fails to Confirm Event-Free Survival, Should the Latter Be Used to Set the Standard of Care?

TO THE EDITOR: We suggest that the far-reaching conclusion based on a landmark phase III trial concerning high-risk neuroblastoma (HR-NB) should be reconsidered, given the major statistical error in the recent update. 1 The initial report in 1999 prompted the worldwide adoption of myeloablative therapy with autologous stemcell transplantation (ASCT) as the standard of care for patients with HR-NB in first remission. Now, 15 years later, we learn that this intervention made no statistically significant difference in overall survival (OS) when tested in a randomized fashion (P .39 by log rank; P.08 at 5 years). 1 OS stands out as the gold standard for evaluation of treatment efficacy, the acid test for US Food and Drug Administration drug approval, and the driving force for advances in cancer therapeutics. 2 OS is 100% accurate for event and time; it takes into account both safety(toxiccomplications)andefficacy.Event-freesurvival(EFS)isa surrogateendpointthatallowsanearlierassessmentofresults,butits validity requires confirmation, either through correlation with OS or by meta-analysis. 2-4 Unless improvement in quality of life can be documented, delaying asymptomatic events without prolonging survival is not clinically meaningful. 3 In short, a surrogate end point should be used with caution as the basis to establish standard of care. In this landmark study, 1 why did OS fail to show significance, whileEFSdid?Thisdiscrepancypointstothewelcomepossibilitythat,