Background In the west, survival following treatment of childhood acute lymphoblastic leukaemia (ALL) approaches 90%. Outcomes in India do not exceed 70%. To address this disparity, the Indian Collaborative Childhood Leukaemia group (ICiCLe) developed in 2013 a contemporary treatment protocol for uniform risk-stratified management of first presentation ALL based on cytogenetics and minimal residual disease levels (MRD). A multicentre randomised clinical trial opened in 2016 (ICiCLe-ALL-14) and examines the benefit of randomised interventions to decrease toxicity and improve outcomes. Methods Patients 1–18 years with newly diagnosed ALL are categorised into four risk groups based on presentation features, tumour genetics and treatment response. Standard risk includes young (< 10 years) B cell precursor ALL (BCP-ALL) patients with low presentation leucocyte count (< 50 × 109/L) and no high-risk features. Intermediate risk includes BCP-ALL patients with no high-risk features but are older and have high presentation leucocyte counts and/or bulky disease. High risk includes BCP-ALL patients with any high-risk feature, including high-risk genetics, central nervous system leukaemia, poor prednisolone response at treatment day 8 and high MRD (≥ 0·01%) at the end of induction. Patients with T-lineage ALL constitute the fourth risk group. All patients receive four intensive treatment blocks (induction, consolidation, interim maintenance, delayed intensification) followed by 96 weeks of maintenance. Treatment intensity varies by risk group. Clinical data management is based on a web-based remote data capture system. The first randomisation examines the toxicity impact of a shorter induction schedule of prednisolone (3 vs 5 weeks) in young non-high-risk BCP-ALL. The second randomisation examines the survival benefit of substituting doxorubicin with mitoxantrone in delayed intensification for all patients. Primary outcome measures include event-free survival (overall, by risk groups), sepsis rates in induction (first randomisation) and event-free survival rates following second randomisation. Discussion ICiCLe-ALL-14 is the first multicentre randomised childhood cancer clinical trial in India. The pre-trial phase allowed standardisation of risk-stratification diagnostics and established the feasibility of collaborative practice, uniform treatment, patient enrolment and data capture. Pre-trial observations confirm the impact of risk-stratified therapy in reducing treatment-related deaths and costs. Uniform practice across centres allows patients to access care locally, potentially decreasing financial hardship and dislocation. Trial registration Clinical Trials Registry-India (CTRI) CTRI/2015/12/006434. Registered on 11 December 2015
Background The biotherapeutic asparaginase is a cornerstone of therapy in acute lymphoblastic leukaemia (ALL). With limited access to the original native Escherichia coli‐derived asparaginase (EcASNase), a variety of EcASNase biogenerics are used in low‐middle‐income countries (LMICs). The variable quality of these biogenerics potentially influences clinical outcomes. Procedure Seven biogeneric EcASNases (P1–P7) marketed widely in India were evaluated, with P2 as an exemplar for in vivo monitoring. Therapeutic activity of P2 (10,000 IU/m2/dose, intramuscular, every 72 hours) was monitored during induction therapy, and drug‐related toxicities recorded. Molecular identity, purity and in vitro drug activity of seven biogenerics were characterised using multimodal analyses, and findings compared with reference EcASNase (R). Results In patients (N = 62) receiving P2, subtherapeutic asparaginase activity (<100 U/L) was observed in 66% (46/70) of trough timepoints (72 hours postdose) during induction. Twelve patients (19%), 11 with high‐risk ALL, developed hypersensitivity. Isoforms of EcASNase were identified in all seven biogenerics. All generic products contained impurities with batch‐to‐batch variability. These included high levels of protein aggregates and host cell protein contamination. In vitro assays of EcASNase activity and leukaemia cell line cytotoxicity were not discriminatory. Conclusions Our findings confirm widespread concerns over the unsatisfactory quality and therapeutic activity of native EcASNase biogenerics marketed in LMICs. Appropriate use of these products requires monitored studies to identify clinical suitability and determine appropriate dosing and schedule. For large parts of the world, assured access to high‐quality asparaginases remains an unmet therapeutic need.
Background and purpose: In pediatric renal tumors, conventional two opposing photon beams have been used to cover the postoperative flank target volume for decades. This single center study describes the locoregional outcome using highly conformal flank target volumes adjusted for postoperative changes and intra-fraction motion combined with Volumetric-Modulated Arc Therapy (VMAT). Materials and methods: Between 01-2015 and 12-2019, 36/161 newly diagnosed patients with renal tumors underwent flank only irradiation (n = 30) or flank + whole lung irradiation (n = 6) using highly conformal target volumes in line with the SIOP-RTSG consensus statement. VMAT consisted of full-arc 10MV photon beams optimized for constraints of the organs at risk. In case of locoregional relapses, image co-registration and dose reconstruction was performed. Each relapse was classified as either 'infield' (V95% relapse : 99.0%), 'marginal' (V95% relapse : 20.0-98.9%) or 'outfield' (V95% relapse : 0-19.9%). Results: At a median follow-up from diagnosis of 3.1 years (range:0.4-5.7), the estimated 2-year Locoregional Control Rate, Disease-Free Interval and Overall Survival were 94%, 91% and 94%, respectively. Locoregional relapse was observed in two patients. One patient had a combined tumor bed and regional recurrence, classified as infield (V95% relapse : 100%) and outfield (V95% relapse : 1.2%). The second patient had a regional relapse in the inferior vena cava classified as marginal recurrence (V95% relapse : 93%). Relapses would not have been adequately covered by conventional beams. Conclusions: This single center analysis provides encouraging evidence that excellent locoregional control can be obtained by using highly conformal flank target volumes with VMAT in pediatric renal tumors. The safety of this approach will be validated in a prospective multicenter study.
Around 6% of all childhood malignancies represent renal tumors, of which a majority includes Wilms tumor (WT). Although survival rates have improved over the last decades, specific patients are still at risk for adverse outcome. In the Netherlands, since 2015, pediatric oncology care for renal tumors has been centralized in the Princess Máxima Center for Pediatric Oncology. Here, we describe experiences of the first 5 years of centralized care and explore whether this influences the epidemiological landscape by comparing data with the Netherlands Cancer Registry (NCR). We identified all patients <19 years with a renal mass diagnosed between 01-01-2015 and 31-12-2019 in the Princess Máxima Center. Epidemiology, characteristics and management were analyzed. We identified 164 patients (including 1 patient who refused consent for registration), in our center with a suspicion of a renal tumor. The remaining 163 cases included WT (n = 118)/cystic partially differentiated nephroblastoma (n = 2)/nephrogenic rests only (n = 6) and non-WT (n = 37). In this period, the NCR included 138 children, 1 17-year-old patient was not referred to the Princess Máxima Center. Central radiology review (before starting treatment) was performed in 121/163 patients, and central pathology review in 148/152 patients that underwent surgery. Treatment stratification, according to SIOP/EpSSG protocols was pursued based on multidisciplinary consensus. Preoperative chemotherapy was administered in 133 patients, whereas 19 patients underwent upfront surgery. Surgery was performed in 152 patients, and from 133 biomaterial was stored. Centralization of care for children with renal tumors led to referral of all but 1 new renal tumor cases in the Netherlands, and leads to referral of very rare subtypes not registered in the NCR, that benefit from high quality diagnostics and multidisciplinary decision making. National centralization of care led to enhanced development of molecular diagnostics and other innovation-based treatments for the future.
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