Key Points
Question
Is the long-term efficacy of adjuvant 3-cycle carboplatin, etoposide, and vincristine (CEV) regimen considered noninferior to the standard 6-cycle CEV regimen in patients with pathologically high-risk retinoblastoma?
Findings
In this noninferiority randomized clinical trial of 187 patients with a median follow-up of 79.0 months, 5-year disease-free survival for patients receiving 3-cycle and 6-cycle CEV was 90.4% and 89.2%, respectively. The difference met the noninferiority margin criterion of 12%.
Meaning
A 3-cycle CEV regimen demonstrated noninferiority compared with a 6-cycle approach and was and proved to be an efficacious adjuvant chemotherapy regimen for individuals diagnosed with pathologically high-risk retinoblastoma.
Abstract
Importance
Adjuvant 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.
Objective
To assess whether 3 cycles of CEV chemotherapy is noninferior to 6 cycles for enucleated unilateral retinoblastoma with high-risk pathological features.
Design, Setting, and Participants
This double-center, randomized, open-label, noninferiority trial was conducted at 2 premier eye centers in China and 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) between August 2013 and March 2024. The final date of follow-up was March 21, 2024.
Interventions
Patients were randomly assigned to receive either 3 (n = 94) or 6 (n = 93) cycles of CEV chemotherapy regimen after enucleation.
Main Outcomes and Measures
The primary end point was disease-free survival, with a noninferiority margin of 12%. Secondary end points encompassed overall survival, safety, economic burden, and the quality of life of children.
Results
All 187 patients (median [IQR] age, 25.0 [20.0-37.0] months; 83 [44.4%] female) completed the trial. Median (IQR) follow-up was 79.0 (65.5-102.5) months. Five-year disease-free survival was 90.4% for the 3-cycle group vs 89.2% for the 6-cycle group (difference, 1.2% [95% CI, −7.5% to 9.8%]), which met the noninferiority criterion (P = .003 for noninferiority). The 6-cycle group experienced a higher frequency of adverse events, greater reduction in quality of life scores, and increased costs compared with the 3-cycle group.
Conclusions and Relevance
Among patients with unilateral pathologic high-risk retinoblastoma, 3 cycles of CEV chemotherapy resulted in 5-year disease-free survival that was noninferior to 6 cycles of CEV chemotherapy.
Trial Registration
ClinicalTrials.gov Identifier: NCT01906814
This randomized clinical trial examines whether 3 cycles of carboplatin, etoposide, and vincristine chemotherapy is noninferior to 6 cycles for enucleated unilateral retinoblastoma with high-risk pathological features.
Introduction
Retinoblastoma is the most common intraocular malignancy affecting infants, with an estimated 8000 new cases globally each year. The introduction of chemotherapy has increased survival rates, particularly among patients with high-risk pathological features,1,2,3 underscoring the importance of postoperative adjuvant chemotherapy.
Despite the benefits of chemotherapy, the optimal number of postoperative adjuvant cycles for high-risk retinoblastoma remains unclear due to scant randomized clinical trial data.4 The current standard practice typically involves 6 cycles of CEV (carboplatin, etoposide, and vincristine) chemotherapy, a regimen adopted from other oncology fields.3,5,6 However, the general consensus is that chemotherapy should be provided in the minimal effective dosage to ensure its anticancer benefits while reducing adverse effects.
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,7,8 as well as financial strain due to treatment-related costs. Previous research indicated that a 3-cycle chemotherapy regimen could offer comparable survival to the standard 6-cycle treatment,8 as observed in early-stage ovarian cancer, suggesting similar efficacy with fewer cycles.9
The aim of this clinical trial was to assess whether a 3-cycle CEV regimen of adjuvant chemotherapy was noninferior to a 6-cycle regimen in patients with high-risk pathological features.
Methods
Study Design
Patients were enrolled from 2 premier eye centers in China to participate in an open-label, double-center, prospective, randomized noninferiority trial (eTable 1 in Supplement 1). The study protocol and statistical analysis plan are provided in Supplement 2. The trial was carried out according to the principles of Good Clinical Practice guideline and the Declaration of Helsinki, as defined by the International Conference on Harmonisation, including compliance with relevant regulations. The study protocol was approved by the institutional ethics review board at each participating center. Written informed consent was obtained from all patients’ guardians. The trial followed the Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines.
Participants
The eligibility criteria included unilateral retinoblastoma with histologically confirmed high-risk pathological features, as defined by the International Retinoblastoma Staging10 (stage I), and specific classifications of the American Joint Committee on Cancer pathological11 pT3a, pT3b, and pT3c, which correspond to massive choroidal infiltration, retrolaminar optic nerve invasion, and scleral infiltration, respectively. Histological sections from the enucleated eyes were subject to independent central review by a panel of 3 experienced pathologists (P. Z., L. J. T., and Y.W. B.), with additional expert pathology reviews conducted at each center.
Key exclusion criteria included any prior treatment for retinoblastoma, such as radiotherapy, chemotherapy, or eye surgery; clinically evident extraocular infiltration detected through orbital computed tomography scanning or magnetic resonance imaging; and any evidence of distant metastasis.
Randomization and Masking
Randomization was managed through a central computer system at the Clinical Research Center of Zhongshan Ophthalmic Center, utilizing a computer-generated random number code. The process was stratified by the trial center to ensure balanced patient distribution, with a 1:1 ratio and block sizes of 4, known only to the statistician. Participants were randomized to the 3-cycle group, receiving the 3-cycle CEV regimen, or the 6-cycle group, receiving the 6-cycle CEV regimen. The statisticians were blinded to treatment assignment to ensure unbiased analysis. After completing the screening, investigators received the treatment assignments from the study coordinator and assigned the corresponding chemotherapy interventions to the patients.
Procedures
Eligible patients were randomly assigned to receive either 3 or 6 cycles of CEV regimens3: vincristine 0.05 mg/kg (or 1.5 mg/m2 for children aged ≥3 years) on day 1, carboplatin 18.6 mg/kg (or 560 mg/m2 for children aged ≥3 years) on day 1, etoposide 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 (21 days).12
Treatment initiation occurred within 21 days after enucleation. Prior to enucleation, patients underwent comprehensive ophthalmic examinations, which included ocular ultrasonography, fundus photography, computed tomography scan, or magnetic resonance imaging. Auditory brainstem evoked potential test was mandatory at screening. Laboratory tests, including complete blood cell count and serum chemistry, were conducted within 3 days before the commencement of each chemotherapy cycle. After CEV chemotherapy, patients were followed up every 3 months for the first 2 years and then every 6 months thereafter. Follow-up assessments aimed to identify signs of recurrence or metastasis and encompassed clinical examinations, fundus photography, ocular ultrasonography, and auditory brainstem evoked potential tests.
Toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (version 5.0). Health-related quality of life was measured using the Pediatric Quality of Life Inventory 4.0 Generic Core Scales, a standardized assessment instrument in evaluating children with chronic health conditions.13
Outcomes
The primary end point was 5-year disease-free survival, defined as the time elapsed from randomization to the first occurrence of local recurrence, regional relapse, distant metastasis, contralateral retinoblastoma, second primary cancer, or death from any cause. The secondary end points comprised overall survival (time from randomization to death as a result of any cause), safety, economic burden due to chemotherapy, and patient quality of life.
Economic costs, including both direct (chemotherapy, surgery, supportive care, examinations) and indirect (accommodation, transport, diet, loss of parental income), were converted to Chinese Yuan. The economic burden was determined by comparing the reduction in cost for the 3-cycle group vs the 6-cycle group. Data on health-related quality of life were collected using printed questionnaires administered before chemotherapy initiation, at the start of each subsequent chemotherapy course, and during follow-up visits for children older than 2 years. Scores range from 0 to 100, with higher scores indicating better health parameters. Missing more than half of the items in a scale resulted in no score calculation.
Sample Size Calculation
The trial aimed to demonstrate the noninferiority of 3 cycles of adjuvant CEV chemotherapy compared with 6cycles. Assuming a disease-free survival rate of 96% for 6 cycles of CEV chemotherapy and no difference between the groups,3 the study planned for a 5-year patient enrollment period and a 5-year follow-up. According to expert consensus, data from institutional experiences, and published literature, survival rates differ, ranging from 40% in cases of combined postlaminar optic nerve disease along with extensive choroidal and scleral invasion14 to 100% with isolated choroidal invasion,15 so a 12% difference was set as the noninferiority margin. With an 8% dropout rate, the required number of events for the primary analysis was 12, necessitating 178 patients (89 in each group) to achieve 80% power at a 5% 1-sided type I error rate, which is appropriate for a rare disease for which randomized studies are scarce.16
Statistical Analysis
Main analyses were done in the primary analysis population according to their randomization group, regardless of protocol deviations. Analyses were conducted using SAS version 9.4 (SAS Institute Inc), SPSS for Windows version 21.0 (IBM Corp) and R version 4.1.0 (R Foundation for Statistical Computing). Time-to-event data were presented using Kaplan-Meier curves, with time-to-event intervals compared using the log-rank test (primary analysis). Missing time-to-event data due to patient follow-up absence were treated as censored data. Hazard ratios (HRs) and 95% CIs were estimated using a Cox proportional hazard model with treatment group as a factor and stratification according to randomization factors for primary and subgroup analyses where appropriate. The rate difference was calculated by subtracting the rate in the 6 -cycle group from that in the 3 -cycle group. To minimize the probability of false-positive results, we corrected the false discovery rate in multiple comparisons.
The significance of the primary outcome was assessed using 1-sided P values, while other statistical tests used a 2-sided approach, with P <.05 denoting statistical significance. The data analysis was finalized on March 21, 2024, after the predetermined number of events occurred. In the per-protocol analysis, patients were excluded for protocol deviations such as tumor progression or severe comorbidities that needing urgent intervention. Safety assessments were carried out on the safety population, comprising patients who adhered to the treatment protocol as intended.
Results
Patient Characteristics
The study initially screened 729 individuals for eligibility from August 2013 to August 2019 and a total of 187 patients with histologically confirmed high-risk pathological features across 2 sites underwent randomization and were included in the primary analyses. The 3-cycle group included 94 patients and the 6-cycle group included 93 patients (Figure 1). The groups were balanced in demographics and clinical characteristics (Table 1); the median (IQR) age of participants was 25.0 (20.0-37.0) months and 83 (44.4%) were females. By March 21, 2024, no patients were lost to follow-up.
Figure 1. Screening, Randomization, and Patient Flow in a Trial of 3-Cycle Chemotherapy for High-Risk Retinoblastoma.
aInclusion criteria included unilateral retinoblastoma with histologically confirmed high-risk pathological features (massive choroidal infiltration, retrolaminar optic nerve invasion, or scleral infiltration). Exclusion criteria included any prior treatment for retinoblastoma, clinically evident extraocular infiltration, or distant metastasis.
bWithout high-risk pathological features in histopathology central review by a panel of 3 experienced pathologists.
cRequired 6 cycles of chemotherapy.
dRefused chemotherapy: 3 patients discontinued chemotherapy after cycle 3, 1 after cycle 2, and 1 after cycle 5.
Table 1. Baseline Disease Characteristics.
| Variable | No. (%) | |
|---|---|---|
| Three-cycle group (n = 94) | Six-cycle group (n = 93) | |
| Age, median (IQR), mo | 25.0 (19.0-39.0) | 25.0 (21.0-35.0) |
| Hereditary pattern, sporadic | 94 (100.0) | 93 (100.0) |
| Duration of symptoms, median (IQR), mo | 1.0 (0.3-3.3) | 2.0 (0.5-3.0) |
| Presenting symptom | ||
| Leukocoria | 68 (72.3) | 62 (66.7) |
| Strabismus | 1 (1.1) | 5 (5.4) |
| Decreased vision | 6 (6.4) | 4 (4.3) |
| Blind painful eye | 4 (4.3) | 5 (5.4) |
| Red eye | 15 (16.0) | 17 (18.3) |
| International Intraocular Retinoblastoma Classificationa | ||
| Group D | 11 (11.7) | 10 (10.8) |
| Group E | 83 (88.3) | 83 (89.2) |
| AJCC classificationb | ||
| cT2b | 13 (13.8) | 10 (10.8) |
| cT3a | 2 (2.1) | 1 (1.1) |
| cT3b | 34 (36.2) | 30 (32.3) |
| cT3c | 36 (38.3) | 40 (43.0) |
| cT3d | 3 (3.2) | 7 (7.5) |
| cT3e | 4 (4.3) | 5 (5.4) |
| cT4a | 2 (2.1) | 0 |
| Largest tumor base ≤15 mm | 2 (2.1) | 4 (4.3) |
| Tumor thickness ≤10 mm | 8 (8.5) | 12 (12.9) |
| Visual acuity (fix and follow) | 2 (2.1) | 0 |
| Histopathologic risk factors | ||
| Isolated retrolaminar optic nerve invasion | 65 (69.1) | 60 (64.5) |
| Retrolaminar optic nerve invasion with massive choroidal infiltration | 15 (16.0) | 17 (18.3) |
| Isolated massive choroidal infiltration | 9 (9.6) | 12 (12.9) |
| Massive choroidal infiltration with scleral infiltration | 1 (1.1) | 2 (2.2) |
| Scleral infiltration | 1 (1.1) | 0 |
| Massive choroidal infiltration and retrolaminar optic nerve invasion with scleral infiltration | 1 (1.1) | 0 |
| Nonec | 2 (2.1) | 2 (2.1) |
Indicates descriptions according to the International Intraocular Retinoblastoma Classification System: Group D, diffuse disease with significant vitreous or subretinal seeding; Group E, presence of any one or more poor prognosis features.
Indicates descriptions according to the American Joint Committee on Cancer (AJCC) 8th edition TNM classification for retinoblastoma: cT2b, tumors with vitreous seeding and/or subretinal seeding; cT3a, phthisis or prephthisis bulbic; T3b, tumor invasion of the pars plana, ciliary body, lens, zonules, iris or anterior chamber; cT3c, raised intraocular pressure with neovascularization and/or buphthalmos; cT3d, hyphema and/or massive vitreous hemorrhage. cT3e, aseptic orbital cellulitisc; cT4a, radiological evidence of retrobulbar optic nerve involvement or thickening of the optic nerve or involvement of the orbital tissues.
Without high-risk pathological features in histopathology central review by a panel of 3 experienced pathologists.
After randomization, 4 participants withdrew consent due to guardian decisions: 2 in the 3-cycle group chose 6-cycle chemotherapy, 1 in the 3-cycle group refused treatment, and 1 in the 6-cycle group continued their regimen. Additionally, 4 participants were excluded from the study due to histopathological inconsistencies identified after chemotherapy (eTable 2 in Supplement 1). This left a modified intent-to-treat population of 179 (89 in the 3-cycle group and 90 in the 6-cycle group), which was reduced to a per-protocol population of 170 (87 in the 3-cycle group and 83 after the 6-cycle group) after protocol violations (Figure 1). The safety population included all 186 participants who initiated chemotherapy.
Primary Outcome
The median (IQR) follow-up on the last follow-up date (March 21, 2024) was 79.0 (65.5-102.5) months. There were 19 disease-free survival events, with 9 (9.6%) in 3-cycle group and 10 (10.8%) in 6-cycle group. Locoregional failure was identified in 7 patients (4 [4.3%] in 3-cycle group vs 3 [3.2%] in 6-cycle group; P = .71) and distant metastasis was identified in 15 patients (7 [7.4%] in 3-cycle group vs 8 [8.6%] in 6-cycle group; P = .79, eTable 3 in Supplement 1).
The primary outcome of estimated 5-year disease-free survival in the 3-cycle group vs 6-cycle group was 90.4% vs 89.2% (difference, 1.2%; [95% CI, −7.5% to 9.8%]), which met the noninferiority criterion (P = .003 for noninferiority; Figure 2). The HR was 0.89 (95% CI, 0.36-2.20; P = .81) (Figure 3A).
Figure 2. Primary Outcome of 5-Year Disease-Free Survival .
Between-group change for the primary outcome and noninferiority margin. The dotted line represents the noninferiority margin.
Figure 3. Kaplan-Meier Estimates in 187 Patients With High-Risk Retinoblastoma Stratified by the Randomization Group.
The hazard ratios (HRs) and their associated 95% CIs were determined using a Cox proportional-hazards model. The median (IQR) duration of follow-up for disease-free survival was 77.0 (65.0-102.0) months for the 3-cycle group and 84.0 (67.0-104.0) months for the 6-cycle group. The median (IQR) duration of follow-up for overall survival was 77.5 (65.0-102.0) months for the 3-cycle group and 84.0 (67.0-104.0) months for the 6-cycle group.
Secondary Outcome
For the secondary end points, there was no significant difference in the 5-year overall survival between the 3-cycle and 6-cycle groups (91.5% vs 89.3%; HR, 0.78 [95% CI, 0.31 to 1.98]; P = .61; Figure 3B). This finding was consistent in the modified intent-to-treat and per-protocol populations (eFigure 1 in Supplement 1).
Health-related quality of life data were collected from 111 patients older than 2 years, including 48 patients (87.3%) in the 3-cycle group and 56 (96.7%) in the 6-cycle group at the initiation of treatment (eTables 4-10 in Supplement 1). A trend toward less decline in physical, emotional, and social functioning was observed in the 3-cycle group 6 months after the surgical procedure (eTable 11 in Supplement 1). At other points, the quality of life remained consistent across both groups (eFigure 2 in Supplement 1).
The total cost, direct cost, and indirect cost were significantly lower in the 3-cycle group (by 42.4%, 41.2%, and 43.0%, respectively), compared with the 6-cycle group (all P < .001). Direct costs, including those for systemic chemotherapy, operation, supportive treatment, and examinations, were consistently higher in 6-cycle group. Indirect costs, such as accommodation, transport, meals, and lost parental income, were also higher in 6-cycle group (eTable 12 in Supplement 1).
Prespecified Exploratory Analyses
A prespecified subgroup analysis was conducted based on baseline characteristics, and no significant interactions were observed between the treatment groups and the subgroups. Disease-free survival was consistent across all subgroups, including age, sex, type of high-risk pathological factors, number of high-risk pathological factors, International Intraocular Retinoblastoma Classification stages, duration of symptoms, study site (eFigure 3 in Supplement 1), and pathological tumor-node-metastasis (pTNM) staging (eTable 13 and eFigure 4 in Supplement 1). Multivariable analyses confirmed that the number of chemotherapy cycles, specifically the 3-cycle group and the 6-cycle group, was not an independent prognostic factor (eTable 14 in Supplement 1).
Adverse Events
During the treatment regimen, among the safety population, 75 of 93 patients (80.6%) in 3-cycle group experienced 282 toxic events. Conversely, in 6-cycle group, 89 of 93 patients (95.7%) experienced a higher number of toxic events, totaling 681. The incidence of grade 1 or 2 adverse events was significantly lower in the 3-cycle group compared with the 6-cycle group ((73 [78.5%] vs 89 [95.7%]; P < .001).
The cumulative burden of hematological toxicities, including neutropenia and anemia, as well as nonhematological toxicities such as nausea and weight loss, was significantly reduced in the 3-cycle group vs the 6-cycle group (Table 2). Furthermore, the frequency of adverse events linked to neutropenia, nausea, vomiting, and upper respiratory infections was observed to escalate from cycles 1-3 to cycles 4-6 in the 6-cycle group (eTable 15 in Supplement 1).
Table 2. Adverse Events During Treatment (Safety Population).
| No. (%) of patients | No. of events | Cumulative time of toxicity, d | ||||
|---|---|---|---|---|---|---|
| Three-cycle group (n = 93) | Six-cycle group (n = 93) | Three-cycle group (n = 93) | Six-cycle group (n = 93) | Three-cycle group (n = 93) | Six-cycle group (n = 93) | |
| Any grade adverse eventsa | 75 (80.6) | 89 (95.7) | 282 | 681 | 1779 | 6639 |
| Acute toxicities | ||||||
| Grade 1/2 adverse events | 73 (78.5) | 89 (95.7) | 264 | 638 | 1604 | 4372 |
| Hematological | ||||||
| Neutropenia | 38 (40.9) | 53 (57.0) | 49 | 126 | 444 | 1193 |
| Anemia | 10 (10.8) | 18 (19.4) | 11 | 33 | 199 | 659 |
| Thrombocytopenia | 9 (9.7) | 8 (8.6) | 11 | 17 | 95 | 200 |
| Lymphopenia | 4 (4.3) | 5 (5.4) | 6 | 14 | 55 | 126 |
| Nonhematological | ||||||
| Upper respiratory infection | 36 (38.7) | 39 (41.9) | 38 | 60 | 255 | 456 |
| Fever | 36 (38.7) | 38 (40.9) | 38 | 57 | 32 | 49 |
| Vomiting | 16 (17.2) | 27 (29.0) | 35 | 123 | 1 | 3 |
| Nausea | 14 (15.1) | 24 (25.8) | 31 | 110 | 27 | 85 |
| Stomatitis (mucositis) | 10 (10.8) | 7 (7.5) | 14 | 13 | 60 | 52 |
| Diarrhea | 10 (10.8) | 7 (7.5) | 12 | 24 | 9.5 | 18 |
| Weight loss | 8 (8.6) | 21 (22.6) | 14 | 52 | 395 | 1467 |
| Dysphagia | 4 (4.3) | 4 (4.3) | 4 | 6 | 3.5 | 4.5 |
| Hearing impaired | 1 (1.1) | 2 (2.2) | 1 | 3 | 28 | 60 |
| Grade 3/4 adverse events | 10 (10.8) | 9 (9.7) | 18 | 42 | 174 | 415 |
| Hematological | ||||||
| Thrombocytopenia | 5 (5.4) | 8 (8.6) | 5 | 18 | 49 | 182 |
| Neutropenia | 6 (6.5) | 6 (6.5) | 6 | 15 | 57 | 151 |
| Lymphopenia | 1 (1.1) | 1 (1.1) | 1 | 2 | 9 | 24 |
| Anemia | 1 (1.1) | 0 | 1 | 0 | 21 | 0 |
| Nonhematological | ||||||
| Upper respiratory infection | 3 (3.2) | 2 (2.2) | 3 | 4 | 33 | 50 |
| Fever | 2 (2.2) | 1 (1.1) | 2 | 3 | 5 | 8 |
| Late toxicities | ||||||
| Grade 2 dysphasia | 0 | 1 (1.1) | 0 | 1 | 0 | 1852 |
The adverse event grading system rates adverse events from mild (1) to death (5), with 3 or 4 representing severe or potentially life-threatening events.
Regarding late toxicities, 1 patient in the 6-cycle group was diagnosed with grade 2 dysphasia 2 years after enrollment. No treatment-related deaths occurred in either group.
Discussion
Retinoblastoma is the leading cause of intraocular malignancies in children, with an estimated 8000 new cases worldwide each year.17 The disease poses a significant challenge in lower- to middle-income countries such as China and India, with an annual incidence of approximately 1000 new cases.18 Survival rates in low-income countries are markedly lower, ranging from 35% to 77%, in contrast to the 98% rate in high-income countries.19 Globally, about 11.1% of patients are diagnosed at stage pT3,20 which is associated with high-risk pathological features. The histological presence of high-risk factors is important for predicting local recurrence, distant metastasis, and overall survival, dictating further treatment.21
Histopathological factors such as massive choroidal infiltration, retrolaminar optic nerve invasion, and scleral infiltration increase the risk of metastatic spread in retinoblastoma. Although complete tumor removal is possible with enucleation, these invasions can promote hematogenous spread or central nervous system metastases.15 Although chemotherapy is crucial for preventing metastases in individuals with high-risk disease, there is no agreement on the optimal cycle count. The common practice is 6 cycles,3,22 but some research indicates that fewer cycles might be equally effective.12,15,23
In the current study, the 5-year disease-free survival and overall survival rates for the 3-cycle postenucleation chemotherapy group were 90.4% and 91.5%, respectively, aligning with global outcomes for pT3 stage retinoblastoma.24 The results suggest that a 3-cycle regimen could be as effective as the standard 6-cycle treatment regimen, possibly due to inherent or acquired resistance in some tumors.9,25 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.3,26 This implies that a 2-year follow-up may be adequate to detect disease-specific events in retinoblastoma patients with high-risk features.
It is important to consider that the results of this study may not be directly comparable to other studies due to differences in high-risk patient inclusion criteria. For instance, some studies may exclude patients with certain high-risk features,27 which can skew the overall survival data. In the influential Children’s Oncology Group study, patients with limited involvement of the optic nerve head or other specific areas were considered for adjuvant chemotherapy,3 even though they might be classified as low-risk by some standards.23 The American Joint Committee on Cancer pTNM staging system, which was used in this study, helps assess tumor dissemination risk and guide treatment for patients with pT3 stage and high-risk pathological factors.28
The need for adjuvant therapy in cases of choroidal invasion remains a topic of debate. Although some studies suggest that massive choroidal invasion is a risk factor for tumor metastasis,3,23 others indicate that the impact of such invasion on survival may not be as severe.29 In the current study, the survival rate for patients with massive choroidal invasion increased to 100% after chemotherapy, highlighting the potential benefits of adjuvant therapy.
The study further revealed that chemotherapy-related adverse effects were prevalent and escalated with the extension of treatment duration and the number of cycles administered, particularly nausea, vomiting, and weight loss, which are significant adverse effects of cancer treatment.7 Remarkably, 1 patient in the 6-cycle group was diagnosed with dysphasia 2 years after enrollment, highlighting the potential for late toxicities.
Health-related quality of life is a crucial aspect of modern cancer management.30 The study showed that patients who received 3 cycles of chemotherapy had less reduction in physical, emotional, and social functioning parameters 6 months after the operation compared with those who received 6 cycles. This suggests that a shorter chemotherapy regimen may be less disruptive to patients’ daily lives and overall well-being.
Secondary cancers are a severe consequence of chemotherapy,7 with the study recording 1 case of acute lymphocytic leukemia after 8 months of follow-up. The risk of secondary acute myelogenous leukemia is associated with chemotherapy,7 and patients receiving such treatment may be at a higher risk of developing these conditions,31 even after 74 years of chemotherapy.31
Reducing the number of chemotherapy cycles can also alleviate the financial burden on patients’ households. The study found that both direct and indirect costs for chemotherapy were significantly lower in the 3-cycle group, which is particularly important in lower-income countries in which financial stress can be a barrier to treatment adherence.32
Limitations
This trial has several limitations. First, the open-label design might introduce bias, although an independent, blinded committee evaluated clinical outcomes. Second, setting a 12% noninferiority margin is notably substantial. Considering the infrequency of randomized studies due to the rarity of retinoblastoma16 and the wide range of survival rates—from 40% in severe cases with optic nerve and extensive choroidal and scleral invasion14 to 100% in isolated choroidal cases15—the margin was deemed appropriate. Third, the study’s criteria for adjuvant therapy, especially regarding choroidal invasion, are debatable. Although it follows the Children’s Oncology Group guidelines identifying isolated choroidal invasion as a high-risk factor for recurrence,3 further follow-up is needed to clarify the prognosis related to various pathological features.
Conclusions
This is the largest prospective study on adjuvant chemotherapy courses for high-risk retinoblastoma after enucleation. Results show that 3 cycles of CEV chemotherapy are as effective as 6 in preventing metastasis and death, with fewer adverse effects and lower costs. This suggests that 3-cycle chemotherapy could become the new standard for unilateral retinoblastoma with high-risk features, potentially replacing the current 6-cycle approach.
eTable 1. Recruitment by Center
eTable 2. Summary of patient with major inconsistencies on histopathology
eTable 3. The Comparison of Disease-Free Survival Between the 2 Groups
eTable 4. Pretreatment PedsQLTM4.0 score of patients
eTable 5. PedsQL™ 4.0 Scores at 6-Month Post-Operation
eTable 6. PedsQL™ 4.0 Scores at 1-Year Post-Operation
eTable 7. PedsQL™ 4.0 Scores at 2-Year Post-Operation
eTable 8. PedsQL™ 4.0 Scores at 3-Year Post-Operation
eTable 9. PedsQL™ 4.0 Scores at 4-Year Post-Operation
eTable 10. PedsQL™ 4.0 Scores at 5-Year Post-Operation
eTable 11. Scale descriptives for PedsQLTM4.0 score (Difference between 6 months after surgery and baseline)
eTable 12. Economic burden
eTable 13. Outcome According to Pathology Features in Initially Enucleated Patients
eTable 14. Multivariable Analyses of Prognostic Factors by Outcome for Patients
eTable 15. Adverse Events In Cycles 1-3 Versus Cycles 4-6 (Safety Population)
eFigure 1. Kaplan-Meier Estimates in 187 Patients With High-risk Retinoblastoma Stratified by the Randomization Group（modified intent-to-treat and per-protocol population）
eFigure 2. Functioning Scores (Baseline To 5 Years) of PedsQLTM4.0
eFigure 3. Disease-Free Survival According to Subgroup
eFigure 4. Use of Adjuvant Therapy and Outcome According to pTNM Staging in Unilateral Retinoblastoma
Trial protocol and statistical analysis plan
Data sharing statement
References
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
eTable 1. Recruitment by Center
eTable 2. Summary of patient with major inconsistencies on histopathology
eTable 3. The Comparison of Disease-Free Survival Between the 2 Groups
eTable 4. Pretreatment PedsQLTM4.0 score of patients
eTable 5. PedsQL™ 4.0 Scores at 6-Month Post-Operation
eTable 6. PedsQL™ 4.0 Scores at 1-Year Post-Operation
eTable 7. PedsQL™ 4.0 Scores at 2-Year Post-Operation
eTable 8. PedsQL™ 4.0 Scores at 3-Year Post-Operation
eTable 9. PedsQL™ 4.0 Scores at 4-Year Post-Operation
eTable 10. PedsQL™ 4.0 Scores at 5-Year Post-Operation
eTable 11. Scale descriptives for PedsQLTM4.0 score (Difference between 6 months after surgery and baseline)
eTable 12. Economic burden
eTable 13. Outcome According to Pathology Features in Initially Enucleated Patients
eTable 14. Multivariable Analyses of Prognostic Factors by Outcome for Patients
eTable 15. Adverse Events In Cycles 1-3 Versus Cycles 4-6 (Safety Population)
eFigure 1. Kaplan-Meier Estimates in 187 Patients With High-risk Retinoblastoma Stratified by the Randomization Group（modified intent-to-treat and per-protocol population）
eFigure 2. Functioning Scores (Baseline To 5 Years) of PedsQLTM4.0
eFigure 3. Disease-Free Survival According to Subgroup
eFigure 4. Use of Adjuvant Therapy and Outcome According to pTNM Staging in Unilateral Retinoblastoma
Trial protocol and statistical analysis plan
Data sharing statement
