Three vs 6 Cycles of Chemotherapy for High-Risk Retinoblastoma

Ye, Huijing; Xue, Kang; Zhang, Ping; Chen, Rongxin; Zhai, Xiaowen; Ling, Li; Xiao, Wei; Tang, Lijuan; Wang, Hongsheng; Mao, Yuxiang; Ai, Siming; Bi, Yingwen; Liu, Qing; Zou, Yusha; Qian, Jiang; Yang, Huasheng

doi:10.1001/jama.2024.19981

JAMA

2024

DOI: 10.1001/jama.2024.19981

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Three vs 6 Cycles of Chemotherapy for High-Risk Retinoblastoma

Huijing Ye,

Kang Xue,

Ping Zhang

et al.

Abstract: ImportanceAdjuvant therapy is an important and effective treatment for retinoblastoma. However, there is a lack of head-to-head clinical trials comparing 3 vs 6 cycles of CEV chemotherapy (carboplatin, etoposide, and vincristine) for enucleated unilateral retinoblastoma with high-risk pathological features.ObjectiveTo assess whether 3 cycles of CEV chemotherapy is noninferior to 6 cycles for enucleated unilateral retinoblastoma with high-risk pathological features.Design, Setting, and ParticipantsThis double-c… Show more

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Meeting the Unmet Needs in Rare Cancer

Li,

Wang,

Zhao

2024

JAMA

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Retinoblastoma, a rare but aggressive eye cancer in infants and young children, accounts for 2% to 4% of pediatric malignancies globally, with an incidence rate ranging from 1 in 20 000 to 1 in 15 000 children. 1 Approximately 8000 new cases are reported annually across the globe, of which more than 1000 are reported in China. 2,3 Notably, regions with the highest prevalence, such as Asia and Africa, have the highest mortality rates, ranging from 40% to 70%, in stark contrast with the 3% to 5% mortality rate in high-income countries. 2 According to the definition of rare cancers from the European RARECARE project (<6/100 000 people), retinoblastoma is considered a rare cancer with significant unmet clinical needs owing to the limited information available regarding its diagnosis and treatment. 4,5 In 2018, the National Health Commission of China announced the "catalog for the first batch of rare diseases"; retinoblastoma appeared in this list, indicating its priority for policymakers in promoting the treatment of retinoblastoma. As a rare cancer, the number of clinical trials conducted for retinoblastoma is limited, particularly in low-and middle-income countries. Most of the existing research originates from high-income countries. However, high-income countries account for less than 10% of the global retinoblastoma cases, while low-and middleincome countries in Asia, Africa, and Latin America represent more than 80% of the cases. 1 The management of retinoblastoma, especially in highrisk cases, frequently necessitates a multimodal therapeutic approach including surgery, radiation, and systemic chemotherapy. The earliest application of carboplatin, etoposide, and vincristine (CEV) as a postenucleation adjuvant treatment in retinoblastoma was documented in the 2002 study by Honavar et al, which used a 6-cycle CEV regimen and provided the foundational clinical evidence for subsequent trials and clinical practices. 6 However, evidence from 2002 may not be relevant for current clinical practice, particularly with the advancement in ophthalmological surgery. There is global disagreement regarding the postenucleation adjuvant treatment of high-risk retinoblastoma, particularly concerning the administration cycles of CEV. Three of the largest centers in the US and Europe have applied 4-, 6-, and 8-cycle CEV regimens for patients at high risk of extraocular relapse, 7 but no consensus has been reached regarding the therapy cycles to date. Current guidelines of most centers generally recommend 6 cycles of adjuvant therapy consisting of CEV for highrisk patients. 8 Although this regimen has demonstrated efficacy, considerable adverse effects accompany it, including bone marrow suppression, vomiting, and long-term complica-

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Meeting the Unmet Needs in Rare Cancer

Li,

Wang,

Zhao

2024

JAMA

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Three vs 6 Cycles of Adjuvant Chemotherapy for Retinoblastoma

Leahey,

Shah,

Shields

2024

JAMA Ophthalmol

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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 ...

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Three vs 6 Cycles of Chemotherapy for High-Risk Retinoblastoma

Cited by 2 publications

References 31 publications

Meeting the Unmet Needs in Rare Cancer

Meeting the Unmet Needs in Rare Cancer

Three vs 6 Cycles of Adjuvant Chemotherapy for Retinoblastoma

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