Three Cycles of Chemo Noninferior to Six for Rare Childhood Eye Cancer

A shorter regimen of three cycles of adjuvant chemotherapy was noninferior to a standard six-cycle regimen among patients with pathologically high-risk retinoblastoma, a Chinese randomized trial showed.

For children treated with three cycles of carboplatin, etoposide, and vincristine (CEV), the 5-year disease-free survival (DFS) rate was 90.4% versus 89.2% with six cycles, which met the predefined noninferiority margin of 12% (P=0.003), reported Huasheng Yang, PhD, of Sun Yat-sen University and Guangdong Provincial Clinical Research Center for Ocular Diseases in Guangzhou, China, and colleagues.

“This is the largest prospective study on adjuvant chemotherapy courses for high-risk retinoblastoma after enucleation,” Yang and colleagues wrote in JAMA, noting that their findings suggest that three cycles of chemotherapy could become the new standard for unilateral retinoblastoma with high-risk features.

At a median follow-up of 79 months, there were 19 DFS events (nine in the three-cycle group and 10 in the six-cycle group). Locoregional failure was identified in seven patients (four vs three patients in the two groups, respectively) and distant metastasis was identified in 15 patients (seven vs eight patients, respectively).

There was no significant difference in 5-year overall survival rates between the groups receiving three cycles and six cycles (91.5% vs 89.3%; HR 0.78, 95% CI 0.31-1.98, P=0.61).

Yang and team also found that the total costs, direct costs, and indirect costs associated with treatment were significantly lower in the three-cycle group — by 42.4%, 41.2%, and 43%, respectively — compared with the six-cycle group.

In an accompanying commentary in JAMA Ophthalmology, Carol L. Shields, MD, of Thomas Jefferson University in Philadelphia, and colleagues observed that while a 12% noninferiority margin risks failing to detect a true difference between three and six cycles, “we agree with the authors that given the rarity of retinoblastoma and the lack of prospective randomized clinical trials, this was an acceptable compromise.”

They also called the cost of therapy “perhaps the most important secondary endpoint of the trial,” and noted that the financial burden of retinoblastoma therapy “can lead to treatment abandonment and death.”

“Thus, a 3-cycle regimen of CEV has the potential to save lives,” they concluded.

Retinoblastoma is the most common type of eye cancer among young children but it is rare, accounting for about 8,000 new cases globally, with about 200 to 300 occurring in the U.S., according to the American Cancer Society.

The introduction of chemotherapy has increased survival rates, particularly among patients with high-risk pathological features, “underscoring the importance of postoperative adjuvant chemotherapy,” Yang and colleagues wrote.

However, in a second commentary accompanying the study, Ning Li, MD, of the Chinese Academy of Medical Sciences and Peking Union Medical College in Beijing, and colleagues pointed out that there is “global disagreement” regarding adjuvant therapy after enucleation for high-risk retinoblastoma.

Li and colleagues pointed to differences regarding treatment intensity among some of the major hospitals that treat retinoblastoma in the U.S. and Europe. While six cycles of adjuvant CEV for high-risk patients is the standard, the optimal number of postoperative adjuvant cycles for high-risk retinoblastoma remains unclear due to a lack of randomized clinical trial data.

Li’s group suggested that noninferiority trials play a crucial role in improving outcomes among patients with rare diseases like retinoblastoma.

Conducting superiority trials with large sample sizes in rare cancers is “impractical,” they pointed out, while noninferiority trials allow researchers to compare new or alternative treatments with established standards of care, using smaller sample sizes and shorter follow-up durations.

Moreover, beyond demonstrating efficacy, noninferiority trials inform health policy, guide reimbursement decisions, and help establish new standards of care, Li and colleagues wrote. “The findings … that a 3-cycle regimen of chemotherapy was noninferior to 6 cycles could lead to changes in clinical practice, reducing treatment burden and costs without compromising patient outcomes, for patients with retinoblastoma.”

This trial included 187 patients who had undergone enucleation for unilateral retinoblastoma with high-risk pathological features (massive choroidal infiltration, retrolaminar optic nerve invasion, or scleral infiltration) at two premier eye centers in China from August 2013 through March 2024.

The three-cycle group included 94 patients and the six-cycle group included 93 patients. Patients had a median age of 25 months, and 44.4% were girls.

There were more hematological and non-hematological adverse events observed in the six-cycle group, specifically a higher cumulative incidence of neutropenia, anemia, nausea, vomiting, and weight loss.

One patient developed a case of acute lymphocytic leukemia after 8 months of follow-up.

Yang and colleagues also evaluated the effect of the two regimens on quality of life, and observed there was a trend towards less decline in physical, emotional, and social functioning in the three-cycle group 6 months after the surgical procedure.

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