Monoclonal antibodies (mAbs) are part of the standard of care for the treatment of many adult solid tumors. Until recently none have been approved for use in children with solid tumors. Neuroblastoma ...(NB) is the most common extracranial solid tumor in children. Those with high-risk disease, despite treatment with very intensive multimodal therapy, still have poor overall survival. Results of treatment with an immunotherapy regimen using a chimeric (human/mouse) mAb against a cell surface disialoganglioside (GD2) have changed the standard of care for these children and resulted in the first approval of a mAb for use in children with solid tumors. This article will review the use of the various anti-GD2 mAbs in children with NB, methods that have been or are being evaluated for enhancing their efficacy, as well as review other promising antigenic targets for the therapeutic use of mAbs in children with NB.
When a child's cancer progresses beyond current treatment capability, the parents are likely to participate in noncurative treatment decision making. One factor that helps parents to make these ...decisions and remain satisfied with them afterward is deciding as they believe a good parent would decide. Because being a good parent to a child with incurable cancer has not been formally defined, we conducted a descriptive study to develop such a definition.
In face-to-face interviews, 62 parents who had made one of three decisions (enrollment on a phase I study, do not resuscitate status, or terminal care) for 58 patients responded to two open-ended questions about the definition of a good parent and about how clinicians could help them fulfill this role. For semantic content analysis of the interviews, a rater panel trained in this method independently coded all responses. Inter-rater reliability was excellent.
Among the aspects of the definition qualitatively identified were making informed, unselfish decisions in the child's best interest, remaining at the child's side, showing the child that he is cherished, teaching the child to make good decisions, advocating for the child with the staff, and promoting the child's health. We also identified 15 clinician strategies that help parents be a part of making these decisions on behalf of a child with advanced cancer.
The definition and the strategies may be used to guide clinicians in helping parents fulfill the good parent role and take comfort afterward in having acted as a good parent.
The viewpoint of the terminally ill child at the time of an end-of-life decision has not been formally investigated. We identified the preferences of children and adolescents with advanced cancer ...about their end-of-life care and the factors that influenced their decisions.
Pediatric patients 10 or more years of age were interviewed within 7 days of participating in one of the following three end-of-life decisions: enrollment onto a phase I trial (n = 7), adoption of a do not resuscitate order (n = 5), or initiation of terminal care (n = 8). The patient, a parent, and the primary pediatric oncologist were interviewed separately by using open-ended interview questions.
Twenty patients, aged 10 to 20 years (mean, 17 years and 4 months), with a refractory solid tumor (n = 12), brain tumor (n = 4), or leukemia (n = 4) participated. Eighteen patients (90%) accurately recalled all of their treatment options and identified their own death as a consequence of their decision. The factors that were most frequently identified included the following: for patients, caring about others (n = 19 patients); for parents, the child's preferences (n = 18 parents); and for physicians, the patient's prognosis and comorbid conditions (n = 14 physicians).
These children and adolescents with advanced cancer realized that they were involved in an end-of-life decision, understood the consequences of their decision, and were capable of participating in a complex decision process involving risks to themselves and others. The decision factors most frequently reported by patients were relationship based; this finding is contrary to existing developmental theories.
Anti-GD2 mAbs, acting via antibody-dependent cell-mediated cytotoxicity, may enhance the effects of chemotherapy. This pilot trial investigated a fixed dose of a unique anti-GD2 mAb, hu14.18K322A, ...combined with chemotherapy, cytokines, and haploidentical natural killer (NK) cells.
Children with recurrent/refractory neuroblastoma received up to six courses of hu14.18K322A (40 mg/m
/dose, days 2-5), GM-CSF, and IL2 with chemotherapy: cyclophosphamide/topotecan (courses 1,2), irinotecan/temozolomide (courses 3,4), and ifosfamide/carboplatin/etoposide (courses 5,6). Parentally derived NK cells were administered with courses 2, 4, and 6. Serum for pharmacokinetic studies of hu14.18K322A, soluble IL2 receptor alpha (sIL2Rα) levels, and human antihuman antibodies (HAHA) were obtained.
Thirteen heavily pretreated patients (9 with prior anti-GD2 therapy) completed 65 courses. One patient developed an unacceptable toxicity (grade 4 thrombocytopenia >35 days). Four patients discontinued treatment for adverse events (hu14.18K322A allergic reaction, viral infection, surgical death, second malignancy). Common toxicities included grade 3/4 myelosuppression (13/13 patients) and grade 1/2 pain (13/13 patients). Eleven patients received 29 NK-cell infusions. The response rate was 61.5% (4 complete responses, 1 very good partial response, 3 partial responses) and five had stable disease. The median time to progression was 274 days (range, 239-568 days); 10 of 13 patients (77%) survived 1 year. Hu14.18K322A pharmacokinetics was not affected by chemotherapy or HAHA. All patients had increased sIL2Rα levels, indicating immune activation.
Chemotherapy plus hu14.18K322A, cytokines, and NK cells is feasible and resulted in clinically meaningful responses in patients with refractory/recurrent neuroblastoma. Further studies of this approach are warranted in patients with relapsed and newly diagnosed neuroblastoma.
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We evaluated whether combining a humanized antidisialoganglioside monoclonal antibody (hu14.18K322A) throughout therapy improves early response and outcomes in children with newly diagnosed high-risk ...neuroblastoma.
We conducted a prospective, single-arm, three-stage, phase II clinical trial. Six cycles of induction chemotherapy were coadministered with hu14.18K322A, granulocyte-macrophage colony-stimulating factor (GM-CSF), and low-dose interleukin-2 (IL-2). The consolidation regimen included busulfan and melphalan. When available, an additional cycle of parent-derived natural killer cells with hu14.18K322A was administered during consolidation (n = 31). Radiation therapy was administered at the end of consolidation. Postconsolidation treatment included hu14.18K322A, GM-CSF, IL-2, and isotretinoin. Early response was assessed after the first two cycles of induction therapy. End-of-induction response, event-free survival (EFS), and overall survival (OS) were evaluated.
Sixty-four patients received hu14.18K322A with induction chemotherapy. This regimen was well tolerated, with continuous infusion narcotics. Partial responses (PRs) or better after the first two chemoimmunotherapy cycles occurred in 42 of 63 evaluable patients (66.7%; 95% CI, 55.0 to 78.3). Primary tumor volume decreased by a median of 75% (range, 100% complete disappearance-5% growth). Median peak hu14.18K322A serum levels in cycle one correlated with early response to therapy (
= .0154, one-sided
-test). Sixty of 62 patients (97%) had an end-of-induction partial response or better. No patients experienced progressive disease during induction. The 3-year EFS was 73.7% (95% CI, 60.0 to 83.4), and the OS was 86.0% (95% CI, 73.8 to 92.8), respectively.
Adding hu14.18K322A to induction chemotherapy improved early objective responses, significantly reduced tumor volumes in most patients, improved end-of-induction response rates, and yielded an encouraging 3-year EFS. These results, if validated in a larger study, may be practice changing.
Background
Alveolar soft part sarcoma (ASPS) is a rare mesenchymal tumor characterized by ASPL‐TFE3 translocation. Apart from complete surgical resection, there is no standard management strategy.
...Procedure
The clinical data of 69 children and young adults less than 30 years old with ASPS diagnosed from 1980–2014 were retrospectively collected from four major institutions.
Results
Median age at diagnosis was 17 years (range: 1.5–30). Forty‐four (64%) were female. Median follow‐up was 46 months (range: 1–409). Most common primary sites were limbs (58%) and trunk (24%). ASPL‐TFE3 translocation was present in all 26 patients tested. IRS postsurgical staging was I in 19 (28%), II in 7 (10%), III in 5 (7%), and IV in 38 (55%) patients. The 5‐year event‐free survival (EFS) and overall survival (OS) were 38% and 72%, respectively. The 5‐year EFS and OS were 80% and 87%, respectively, for the 31 patients with localized tumors (IRS‐I‐II‐III), and 7% and 61%, respectively, for the 38 patients with metastatic tumors (IRS‐IV). Of 11 IRS‐IV patients who received targeted therapy upfront, two had partial response, six had stable disease, and three had progressive disease. Median time to progression for IRS‐IV patients was 12 months for those treated with targeted therapy, 7 months for cytotoxic chemotherapy (N = 15), and 4 months for observation only (N = 6).
Conclusion
Localized ASPS has a good prognosis after gross total resection. ASPS is resistant to cytotoxic chemotherapy. Although there are no curative therapies for patients with metastatic disease, prolonged disease stabilization may be achieved with targeted therapies.
Little information is available regarding the safety of ultrasound contrast agents in children. The purpose of this article was to assess the safety profile of the i.v. administration of ultrasound ...contrast agents in the pediatric oncology population.
Patients with pediatric solid malignancies who were enrolled on institutional clinical trials conducted between June 2003 and January 2013 and who met our institutional screening criteria for contrast-enhanced ultrasound (CEUS) were eligible. After providing informed consent or assent for CEUS, subjects received i.v. bolus injections of one of two contrast agents for imaging of the primary tumor or a metastatic target lesion. Hemodynamic parameters, including heart rate, cardiac rhythm, and oxygen saturation, were monitored immediately before and for 30 minutes after the administration of the contrast agent. Interviews with the subject or a guardian were conducted by the principal investigator or a radiologist coinvestigator before and after the examination to assess for any adverse effects.
Thirty-four subjects (21 male and 13 female) ranging in age from 8 months to 20.7 years (median, 8.7 years) underwent 134 CEUS. No detrimental change in hemodynamic status occurred in any subject. Three subjects (3/134, 2.2%) reported mild transient side effects on one occasion each, two (2/134, 1.5%) had taste alteration, and one (1/134, 0.8%) reported mild transient tinnitus and lightheadedness. These reactions did not recur in these subjects on subsequent CEUS examinations.
The i.v. administration of ultrasound contrast agents is safe and well tolerated in the pediatric oncology population. Further studies in children are needed to confirm our findings.
Treatment outcome for black patients with cancer has been significantly worse than for their white counterparts. We determined whether recent improved treatment had narrowed the gap in outcome ...between black and white pediatric patients.
In a parallel comparison, we analyzed survival by disease category between black and white patients with childhood cancer registered in one of the 17 cancer registries of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) program or treated at St Jude Children's Research Hospital, which provides comprehensive treatment to all patients regardless of their ability to pay, from 1992 to 2000 and from 2001 to 2007.
Analysis of the SEER data indicated that in both study periods, black patients had significantly poorer rates of survival than did white patients, with the exception of a few types of cancer. Despite significantly improved treatment outcomes for patients who were treated from 2001 to 2007, the racial difference in survival has actually widened for acute myeloid leukemia and neuroblastoma. By contrast, in the cohorts treated at St Jude Children's Research Hospital, there were no significant differences in survival between black and white patients in either study period, regardless of the cancer type. Importantly, the outcome of treatment for acute lymphoblastic leukemia, acute myeloid leukemia, and retinoblastoma has improved in parallel for both races during the most recent study period.
With equal access to comprehensive treatment, black and white children with cancer can achieve the same high cure rates.
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