3 cycles of chemo enough for high-risk retinoblastoma in children

Shortening the postenucleation chemotherapy regimen containing carboplatin, etoposide, and vincristine (CEV) from six to three cycles results in comparable survival outcomes in paediatric patients with unilateral pathologic high-risk retinoblastoma, according to new research.

In a cohort of 187 paediatric patients (median age 25.0 months, 44.4 percent female) who had undergone enucleation for unilateral retinoblastoma with high-risk pathological features, the primary endpoint of disease-free survival (DFS) at 5 years was 90.4 percent in the three-cycle group vs 89.2 percent in the six-cycle group (hazard ratio [HR], 0.89, 95 percent confidence interval [CI], 0.36–2.20; p=0.81), meeting the noninferiority criterion (p=0.003). [JAMA 2024;doi:10.1001/jama.2024.19981]

Furthermore, overall survival at 5 years did not significantly differ between the three- and six-cycle groups (91.5 percent vs 89.3 percent; HR, 0.78, 95 percent CI, 0.31–1.98; p=0.61).

“The 5-year disease-free survival and overall survival rates for the three-cycle postenucleation chemotherapy group … align with global outcomes for pT3 stage retinoblastoma. These suggest that a three-cycle regimen could be as effective as the standard six-cycle treatment regimen, possibly due to inherent or acquired resistance in some tumours,” the investigators said. [Ophthalmology 2024;doi:10.1016/j.ophtha.2024.08.037; Gynecol Oncol 2006;102:432-439; Bioinform Biol Insights 2013;7:289-306] 

“All disease-specific events in this study occurred within 20 months, and other studies have noted all events within the first year of follow-up, with a recurrence to death time of about 8 months. This implies that a 2-year follow-up may be adequate to detect disease-specific events in retinoblastoma patients with high-risk features,” they added. [J Clin Oncol 2019;37:2883-2891; Ophthalmology 2007;114:2083-2089]

In the study, the patients were randomly assigned to receive either three (n=94) or six cycles (n=93) of CEV chemotherapy within 21 days after enucleation. Vincristine was given at 0.05 mg/kg (or 1.5 mg/m² for children aged ≥3 years) on day 1, carboplatin at 18.6 mg/kg (or 560 mg/m² for children aged ≥3 years) on day 1, etoposide at 5.0 mg/kg/d (or 150 mg/ m² for children aged ≥3 years) on days 1 and 2. Cycles were repeated every 3 weeks. The median follow-up was 79.0 months.

Most patients had isolated retrolaminar optic nerve invasion (69.1 percent in the three-cycle group vs 64.5 percent in the six-cycle group), while others had massive choroidal infiltration (1.1 percent vs 2.2 percent, respectively) or scleral infiltration (1.1 percent vs 0 percent). 

Safety, QoL, and healthcare costs

“[Patients in] the six-cycle group experienced a higher frequency of adverse events, greater reduction in quality of life (QoL) scores, and increased costs compared with [those in] the three-cycle group,” the investigators noted.

Any-grade adverse events (AEs) occurred in 80.6 percent of patients in the three-cycle group vs 95.7 percent in the six-cycle group. The most common grade 1/2 haematological AEs were neutropenia (40.9 percent vs 57.0 percent) and anaemia (10.8 percent vs 19.4 percent), whereas the most frequently reported grade 1/2 nonhematological AEs included upper respiratory infection (38.7 percent vs 41.9 percent), fever (38.7 percent vs 40.9 percent), vomiting (17.2 percent vs 19.4 percent), and nausea (15.1 percent vs 25.8 percent).

Grade 3/4 AEs occurred in 10.8 percent of patients in the three-cycle group vs 9.7 percent in the six-cycle group, with the most common being thrombocytopenia (5.4 percent vs 8.6 percent) and neutropenia (6.5 percent vs 6.5 percent).

In terms of health-related QoL, the three-cycle group showed less decline in physical, emotional, and social functioning compared with the six-cycle group at 6 months after enucleation.

Finally, the three-cycle chemo regimen was associated with significantly healthcare cost, including total cost (difference, 42.4 percent), direct cost (ie, systemic chemotherapy, operation, supportive treatment, and examinations; difference, 41.2 percent), and indirect cost (ie, accommodation, transport, meals, and lost parental income; difference, 43.0 percent; p<0.001 for all).

The investigators pointed out that the findings have important implications, given that extended chemotherapy may cause adverse effects such as suppression of bone marrow function, mouth sores, digestive problems, hair loss, and serious complications including organ damage and secondary cancers, as well as financial strain due to treatment-related costs. [Arch Ophthalmol 2008;126:862-865; Curr Eye Res 2016;41:1507-1512]