Three vs 6 Cycles of Adjuvant Chemotherapy for Retinoblastoma

Abstract

In this issue of JAMA, Ye and colleagues 1 report the results of their dual-institution randomized clinical trial of 3 cycles vs 6 cycles of standard-dose carboplatin etoposide vincristine (CEV) as adjuvant chemotherapy for pT3a (massive choroidal infiltration), pT3b (retrolaminar optic nerve invasion), and pT3c (scleral invasion) in patients with group D and E retinoblastoma undergoing upfront enucleation. Of 187 patients who underwent randomization, there were 179 included in the modified intention-to-treat analysis (4 guardians withdrew consent, and 4 patients were found not to have pT3a-c pathology on subsequent review). Substantial strengths of this trial included a median follow-up of 6.5 years, and no study participants were lost to follow-up.The primary end point of the trial was whether 5-year disease-free survival with a 3-cycle regimen was noninferior to a 6-cycle regimen with an 80% power at a 5% 1-sided type I error rate. The 5-year disease-free survival for patients receiving 3 cycles (n = 89) was 90% compared with 89% in the 6-cycle group (n = 90). The majority of patients who developed recurrent disease (n = 19) did so with evidence of central nervous system (CNS) disease, which is associated with a less than 5% survival rate. Overall survival was a secondary end point of the study and was found to be 92% and 89% in the 3-and 6-cycle groups, respectively. In comparison, a prospective Children's Oncology Group (COG) study of 102 patients who received 6 cycles of standard dose CEV as adjuvant therapy demonstrated a 2-year eventfree survival of 96% and a 2-year overall survival of 97%. 2 The authors of the present study 1 correctly point out that 15 of the patients in the COG study had nonmassive choroidal invasion with concomitant laminar or prelaminar optic nerve invasion, a group who would not receive adjuvant therapy in 2024. However, the COG study also included a group of 3 patients who had 0% survival rate, namely those with postlaminar optic nerve invasion of 1.8 mm or greater with concomitant 4 mm or greater choroidal invasion. Standard care for these highest-risk patients typically is more intensive therapy.Perhaps the most important secondary end point was the cost of therapy. The authors studied both direct costs of therapy (chemotherapy, examinations, supportive care) as well as indirect costs such as travel, accommodations, and loss of parental income. Although intuitive, the authors rigorously found that both direct and indirect costs were less in the 3-cycle group. Importantly, the chemotherapy interval in the present study was 21 days compared with the 28-day interval of the aforementioned COG trial. Practically, this means that the 3-cycle regimen given every 21 days can be concluded in 9 weeks instead of 12 weeks. The authors also reported a greater reduction in quality-of-life scores in the 6-cycle group, although the differences were not shown to be statistically significant. A "…trend toward less decline…" 1 without statistical signifi-Three vs 6 Cycles of Adjuvant Chemotherapy ...