Advances in neuroblastoma therapy MacFarland, Suzanne; Bagatell, Rochelle
Current opinion in pediatrics,
02/2019, Letnik:
31, Številka:
1
Journal Article
Recenzirano
Our understanding of the biologic basis of neuroblastoma, the genetic heterogeneity of this malignancy and the role of host factors has expanded significantly in recent years. In this review, we ...highlight current and future risk-based treatment approaches and discuss the opportunities and challenges of selecting optimal therapies for specific patient subsets.
Significant progress has been made in understanding neuroblastoma predisposition and new approaches have been taken to treatment of this disease. Although survival remains poor for patients with high-risk neuroblastoma, current-era therapy has improved outcomes. Integration of new prognostic markers into neuroblastoma classification systems will allow more precise risk classification and refined treatment assignment. Promising treatments that include targeted therapies as well as immunotherapeutics are being evaluated in clinical trials, and new predictive biomarkers are being developed.
As our understanding of neuroblastoma biology deepens, our approaches to therapy for this disease continue to evolve. Improved risk stratification and the use of predictive biomarkers will aid in treatment selection for patients with neuroblastoma, and it is expected that future treatments will be associated with greater efficacy and less toxicity.
Treatment planning for children with neuroblastoma requires accurate assessment of prognosis. The most recent Children's Oncology Group (COG) risk classification system used tumor stage as defined by ...the International Neuroblastoma Staging System. Here, we validate a revised classifier using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporate segmental chromosome aberrations (SCA) as an additional genomic biomarker.
Newly diagnosed patients enrolled on the COG neuroblastoma biology study ANBL00B1 between 2007 and 2017 with known age, International Neuroblastoma Staging System, and INRGSS stage were identified (N = 4,832). Tumor
status, ploidy, SCA status (1p and 11q), and International Neuroblastoma Pathology Classification histology were determined centrally. Survival analyses were performed for combinations of prognostic factors used in COG risk classification according to the prior version 1, and to validate a revised algorithm (version 2).
Most patients with locoregional tumors had excellent outcomes except for those with image-defined risk factors (INRGSS L2) with
amplification (5-year event-free survival and overall survival: 76.3% ± 5.8% and 79.9% ± 5.5%, respectively) or patients age ≥ 18 months with L2
nonamplified tumors with unfavorable International Neuroblastoma Pathology Classification histology (72.7% ± 5.4% and 82.4% ± 4.6%), which includes the majority of L2 patients with SCA. For patients with stage M (metastatic) and MS (metastatic, special) disease, genomic biomarkers affected risk group assignment for those < 12 months (
) or 12-18 months (
, histology, ploidy, and SCA) of age. In a retrospective analysis of patient outcome, the 5-year event-free survival and overall survival using COG version 1 were low-risk: 89.4% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 86.1% ± 1.3% and 94.9% ± 0.8%; high-risk: 50.8% ± 1.4% and 61.9% ± 1.3%; and using COG version 2 were low-risk: 90.7% ± 1.1% and 97.9% ± 0.5%; intermediate-risk: 85.1% ± 1.4% and 95.8% ± 0.8%; high-risk: 51.2% ± 1.4% and 62.5% ± 1.3%, respectively.
A revised 2021 COG neuroblastoma risk classifier (version 2) that uses the INRGSS and incorporates SCAs has been adopted to prospectively define COG clinical trial eligibility and treatment assignment.
Neuroblastoma Maris, John M, MD; Hogarty, Michael D, MD; Bagatell, Rochelle, MD ...
The Lancet (British edition),
06/2007, Letnik:
369, Številka:
9579
Journal Article
Recenzirano
Summary The clinical hallmark of neuroblastoma is heterogeneity, with the likelihood of cure varying widely according to age at diagnosis, extent of disease, and tumour biology. A subset of tumours ...will undergo spontaneous regression while others show relentless progression. Around half of all cases are currently classified as high-risk for disease relapse, with overall survival rates less than 40% despite intensive multimodal therapy. This Seminar focuses on recent advances in our understanding of the biology of this complex paediatric solid tumour. We outline plans for the development of a uniform International Neuroblastoma Risk Group (INRG) classification system, and summarise strategies for risk-based therapies. We also update readers on new discoveries related to the underlying molecular pathogenesis of this tumour, with special emphasis on advances that are translatable to the clinic. Finally, we discuss new approaches to treatment, including recently discovered molecular targets that might provide more effective treatment strategies with the potential for less toxicity.
Summary Background Outcomes for children with relapsed and refractory neuroblastoma are dismal. The combination of irinotecan and temozolomide has activity in these patients, and its acceptable ...toxicity profile makes it an excellent backbone for study of new agents. We aimed to test the addition of temsirolimus or dinutuximab to irinotecan–temozolomide in patients with relapsed or refractory neuroblastoma. Methods For this open-label, randomised, phase 2 selection design trial of the Children's Oncology Group (COG; ANBL1221), patients had to have histological verification of neuroblastoma or ganglioneuroblastoma at diagnosis or have tumour cells in bone marrow with increased urinary catecholamine concentrations at diagnosis. Patients of any age were eligible at first designation of relapse or progression, or first designation of refractory disease, provided organ function requirements were met. Patients previously treated for refractory or relapsed disease were ineligible. Computer-based randomisation with sequence generation defined by permuted block randomisation (block size two) was used to randomly assign patients (1:1) to irinotecan and temozolomide plus either temsirolimus or dinutuximab, stratified by disease category, previous exposure to anti-GD2 antibody therapy, and tumour MYCN amplification status. Patients in both groups received oral temozolomide (100 mg/m2 per dose) and intravenous irinotecan (50 mg/m2 per dose) on days 1–5 of 21-day cycles. Patients in the temsirolimus group also received intravenous temsirolimus (35 mg/m2 per dose) on days 1 and 8, whereas those in the dinutuximab group received intravenous dinutuximab (17·5 mg/m2 per day or 25 mg/m2 per day) on days 2–5 plus granulocyte macrophage colony-stimulating factor (250 μg/m2 per dose) subcutaneously on days 6–12. Patients were given up to a maximum of 17 cycles of treatment. The primary endpoint was the proportion of patients achieving an objective (complete or partial) response by central review after six cycles of treatment, analysed by intention to treat. Patients, families, and those administering treatment were aware of group assignment. This study is registered with ClinicalTrials.gov , number NCT01767194 , and follow-up of the initial cohort is ongoing. Findings Between Feb 22, 2013, and March 23, 2015, 36 patients from 27 COG member institutions were enrolled on this groupwide study. One patient was ineligible (alanine aminotransferase concentration was above the required range). Of the remaining 35 patients, 18 were randomly assigned to irinotecan–temozolomide–temsirolimus and 17 to irinotecan–temozolomide–dinutuximab. Median follow-up was 1·26 years (IQR 0·68–1·61) among all eligible participants. Of the 18 patients assigned to irinotecan–temozolomide–temsirolimus, one patient (6%; 95% CI 0·0–16·1) achieved a partial response. Of the 17 patients assigned to irinotecan–temozolomide–dinutuximab, nine (53%; 95% CI 29·2–76·7) had objective responses, including four partial responses and five complete responses. The most common grade 3 or worse adverse events in the temsirolimus group were neutropenia (eight 44% of 18 patients), anaemia (six 33%), thrombocytopenia (five 28%), increased alanine aminotransferase (five 28%), and hypokalaemia (four 22%). One of the 17 patients assigned to the dinutuximab group refused treatment after randomisation; the most common grade 3 or worse adverse events in the remaining 16 patients evaluable for safety were pain (seven 44% of 16), hypokalaemia (six 38%), neutropenia (four 25%), thrombocytopenia (four 25%), anaemia (four 25%), fever and infection (four 25%), and hypoxia (four 25%); one patient had grade 4 hypoxia related to therapy that met protocol-defined criteria for unacceptable toxicity. No deaths attributed to protocol therapy occurred. Interpretation Irinotecan–temozolomide–dinutuximab met protocol-defined criteria for selection as the combination meriting further study whereas irinotecan–temozolomide–temsirolimus did not. Irinotecan–temozolomide–dinutuximab shows notable anti-tumour activity in patients with relapsed or refractory neuroblastoma. Further evaluation of biomarkers in a larger cohort of patients might identify those most likely to respond to this chemoimmunotherapeutic regimen. Funding National Cancer Institute.
Molecular chaperones or so-called heat shock proteins serve as central integrators of protein homeostasis within cells. In performing this function, they guide the folding, intracellular disposition, ...and proteolytic turnover of many key regulators of cell growth, differentiation, and survival. Recent data show essential roles for the chaperones in facilitating malignant transformation at the molecular level and support the concept that their altered utilization during oncogenesis is critical to the development of human cancers. The field is evolving rapidly, but it has become apparent that chaperones can serve as biochemical buffers at the phenotypic level for the genetic instability that is characteristic of many human cancers. Chaperone proteins thus allow tumor cells to tolerate the mutation of multiple critical signaling molecules that would otherwise be lethal. Much of the recent progress in understanding the complex role of heat shock proteins in tumorigenesis has been made possible by the discovery of several natural product antitumor antibiotics that selectively inhibit the function of the chaperone Hsp90. These agents have been used as probes to define the biological functions of Hsp90 at the molecular level and to validate it as a novel target for anticancer drug action. One of these agents, 17-allylamino,17-demethoxygeldanamycin (NSC 330507) has begun phase II clinical trials, and several second-generation compounds are now in late preclinical development. The best way to use Hsp90 inhibitors as anticancer agents remains to be defined. Trials accomplished to date, however, serve as proof of principle that Hsp90 function can be modulated pharmacologically without undue toxicity in humans. Given the redundancy and complexity of the signaling pathway abnormalities present in most cancers, the ability of Hsp90 inhibitors to alter the activity of multiple aberrant signaling molecules instead of just one or two (as most current-generation molecular therapeutics have been designed to do) may prove of unique therapeutic benefit.
Purpose
High dose methotrexate (HDMTX) acute kidney injury (AKI) results in prolonged hospitalization and treatment delays. Using a pharmacologically-based approach, HDMTX was administered with ...standard combination therapy to patients with osteosarcoma; nephrotoxicity was assessed.
Methods
Patients were randomized by cycle to 4 h or 12 h HDMTX (12 g/m
2
) infusions administered with hydration, alkalization and leucovorin rescue. Urinalysis, AKI biomarkers, and estimated glomerular filtration rate using serum creatinine or cystatin C (GFR
Cr
or GFR
cysC
) were obtained. Serum and urine methotrexate concentrations MTX were measured.
Results
Patients (
n
= 12), median (range) age 12.4 (5.7–19.2) years were enrolled; 73 MTX infusions were analyzed. Median (95% Confidence Interval) serum and urine MTX were 1309 (1190, 1400) µM and 16.4 (14.7, 19.4) mM at the end of 4 h infusion and 557 (493, 586) µM and 11.1 (9.9, 21.1) mM at the end of 12 h infusion. Time to serum MTX < 0.1 µM was 83 (80.7, 90.7) h and 87 (82.8, 92.4) h for 4 and 12 h infusions. GFR
Cr
was highly variable, increased after cisplatin, and exceeded 150 ml/min/1.73 m
2
. GFR
cysC
was less variable and decreased at the end of therapy. AKI biomarkers were elevated indicating acute tubular dysfunction, however, did not differ between 4 and 12 h infusions. Radiographic and histological response were similar for patients receiving 4 h or 12 h infusions; the median percent tumor necrosis was > 95%.
Conclusions
Reducing peak serum and urine MTX concentration by prolonging the infusion duration did not alter risk of acute kidney injury. GFR
cysC
was decreased at the end of therapy. Proteinuria and elevations in AKI biomarkers indicate that direct tubular damage contributes to HDMTX nephrotoxicity.
Clinical Trial
NCT01848457.
Background
Adverse events (AEs) on Children's Oncology Group (COG) trials are reported manually by clinical research assistants (CRAs). The Common Terminology Criteria for Adverse Events (CTCAE) was ...developed to provide standardized definitions for identifying and grading AEs. The CTCAE has expanded significantly over its five versions, but the impact of CTCAE definitional changes has not been examined.
Procedure
This study compared AE number and ascertainment among the first four CTCAE versions using a case vignette. Each CTCAE version was used to create a list of AEs and grades by two separate CRAs.
Results
The CTCAE expanded from 9 categories and 49 AEs in v1.0 to 26 categories and 790 AEs in v4.0. CRAs independently selected different approaches to AE ascertainment—comprehensive and parsimonious. The number of AEs identified in the parsimonious approach was stable with 10–14 in each CTC version. The comprehensive approach identified 9, 20, 29, and 37 AEs in CTC versions 1.0, 2.0, 3.0, and 4.0, respectively. Only approximately 65% of AEs were conclusively graded in versions 2.0 to 4.0 using the comprehensive approach.
Conclusions
CTCAE has increased in complexity. Although this increased complexity allows for more granular AE reporting, these data demonstrate potential unintended negative consequences of increasing CTC AE complexity, including the risk of varying approaches to AE capture. A comprehensive evaluation of CTC AE definitions and CRA reporting practices across COG institutions and AEs are needed to improve the accuracy and efficiency of AE reporting.
Neuroblastoma is the most common extra‐cranial solid tumor in children and is known for its clinical heterogeneity. A greater understanding of the biology of this disease has led to both improved ...risk stratification and new approaches to therapy. Outcomes for children with low and intermediate risk disease are excellent overall, and efforts to decrease therapy for such patients have been largely successful. Although survival has improved over time for patients with high‐risk disease and treatments evaluated in the relapse setting are now being moved into earlier phases of treatment, much work remains to improve survival and decrease therapy‐related toxicities. Studies of highly annotated biobanked samples continue to lead to important insights regarding neuroblastoma biology. Such studies, along with correlative biology studies incorporated into therapeutic trials, are expected to continue to provide insights that lead to new and more effective therapies. A focus on translational science is accompanied by an emphasis on new agent development, optimized risk stratification, and international collaboration to address questions relevant to molecularly defined subsets of patients. In addition, the COG Neuroblastoma Committee is committed to addressing the patient/family experience, mitigating late effects of therapy, and studying social determinants of health in patients with neuroblastoma.
PDF
