DISCUSSION
Spontaneous tumour regression is well recognised in Infants with low-risk neuroblastoma and favourable biology (i.e. no SCAs and hyperdiploidy).2 The concept of a ‘wait-and-see’ approach has been described previously and avoids the morbidity and mortality associated with chemotherapy and potentially extensive surgery.3,5–11,16 However, there is currently no international consensus about which cases this observational approach is appropriate for, and what criteria should be used to define progression requiring active intervention.
Yamamoto et al. defined criteria for using an observation-only approach for small lesions detected in a Japanese population screening programme in 1998.12 Subsequent publications have cited these same criteria or adapted versions which have generally only included tumours < 5 cm in diameter at diagnosis.
In 2007, the German Society of Paediatric Oncology and Haematology published data showing that spontaneous regression in non-MYCNamplified, localised neuroblastoma may start after 1 year of age, and occur in patients with larger tumours, suggesting that a ‘wait-and-see’ strategy may be more widely appropriate.3
A 2012 Children’s Oncology Group (COG) study demonstrated the safe and effective use of ‘expectant-observation’ in Stage 1 and 2 adrenal tumours in patients less than 6 months old.7 However, this study used conservative tumour diameter cut offs of 3.1 cm or 5 cm for solid and cystic tumours respectively. Additionally, ‘expectant-observation’ was terminated if tumour volume increased by 50% or if catecholamine levels increased above 50% and did not return to baseline within 12 weeks. A phase III COG trial is currently investigating an observational approach using response and biology-based risk factor-guided therapy in infants < 18 months with L2 tumours and favourable biology. In this trial, a 25% increase in tumour volume prompts use of adjuvant therapy.17
In the current case, the initial tumour size and the observed growth (100% increase in anteroposterior diameter, 57% in transverse diameter and 67% in craniocaudal diameter), resulting in a > 3 fold increase in tumour volume, along with 9-10 fold increase in HMMA and HVA, would have precluded a ‘wait-and-see’ strategy based on previous study criteria.6,7,12 Persevering with an observational approach, with parental agreement, in the absence of life- or organ-threatening features, avoided the risks of active treatment while still achieving a positive clinical outcome. However, it is critical to consider patient tumour biology and clinical features before embarking on an observation-only strategy. Utilising pan-genomic techniques such as SNP (single nucleotide polymorphism) arrays and more recently whole genome sequencing (WGS) allows SCAs conferring a higher risk of progression and relapse to be excluded.18 Age at diagnosis is also important as some groups e.g. infants < 2 months of age with MS disease, have the potential for rapid deterioration and may benefit from early treatment regardless of biology.19
This case demonstrates that a ‘wait-and-see’ approach may be more widely applicable than previously used, including tumours > 5 cm in diameter at diagnosis. This case also illustrates that in patients with favourable biology without life- or organ-threatening features, tumour growth and rising catecholamines, do not by themselves preclude safe continuation of an observation-only approach.3
Further work is required to establish international evidence-based criteria to identify subgroups of patients where embarking on an observational approach is appropriate and to review criteria for active treatment when using this initial management strategy.