Key messages
- One well-designed study showed that chemotherapy through an artery compared to a vein is probably better at saving the eye from being removed and probably makes little to no difference to survival. It may make little to no difference to the tumor coming back (recurrence) or to the number of serious or very serious unwanted or harmful events.
- Other less well-designed studies showed that chemotherapy through a combination of vein and artery compared to an artery may make little to no difference in saving the eye from being removed or survival.
- More large, well-designed studies are needed and clear, agreed definitions for study outcomes should be used.
What is retinoblastoma and how is it treated?
Retinoblastoma is the most common eye cancer in children and can also rarely occur in adults. Along with other treatments, chemotherapy delivered through an artery or vein is the main treatment used to shrink the tumor and save the eye and vision.
What did we want to find out?
We wanted to find out the benefits and harms of chemotherapy through an artery compared to a vein in people with retinoblastoma. We also looked at a combination of chemotherapy through an artery and vein compared to an artery. We were mainly interested in tumor control, saving the eye from removal, survival, new cancers that appear after the first cancer, tumor recurrence, cancer spreading to other parts of the body, and the number of serious or very serious unwanted or harmful events.
What did we do?
We searched for studies comparing these treatments, summarized and evaluated the results, and assessed our confidence in the evidence.
What did we find?
We included six studies: three compared chemotherapy through an artery with delivery through a vein (210 participants, 214 eyes); three compared chemotherapy through an artery and vein with delivery through an artery (599 participants, 681 eyes). All participants in the studies were children.
Main results
The main results are for medium-term follow-up of up to three years.
Chemotherapy through an artery compared to through a vein
One study randomly placed participants in groups (143 participants). Chemotherapy through an artery is probably better than through a vein at saving the eye from removal and probably results in little to no difference in survival. It may result in little to no difference in tumor recurrence and may result in little to no difference in the number of serious or very serious unwanted or harmful events.
From the studies that did not randomly place participants in groups (2 studies, 67 participants), the evidence is very uncertain about the effects of chemotherapy through an artery compared to through a vein on tumor control (avoiding surgical removal of the eye) or radiotherapy to target the tumor. New cancers that appear after the first cancer were not reported. It may have little to no effect on cancer spreading to other parts of the body, but the evidence is very uncertain.
Chemotherapy through an artery and vein compared to through an artery
Chemotherapy through an artery and vein compared to delivery through an artery (3 studies, 599 participants) may have little to no effect on tumor control (avoiding surgical removal of the eye) or radiotherapy to target the tumor, but the evidence is very uncertain. It may result in little to no difference in saving the eye from being removed or survival. New cancers that appear after the first cancer were not reported. We do not know about the effects on tumor recurrence, cancer spreading to other parts of the body, or the number of serious or very serious unwanted or harmful events because the evidence is very uncertain.
What are the limitations of the evidence?
Chemotherapy through an artery compared to through a vein
For the study that randomly placed participants into groups, we are moderately confident in the evidence for saving the eye from being removed and survival. Our main reason for less confidence was the small number of participants. We have little confidence in the evidence regarding tumor recurrence and the number of serious or very serious unwanted or harmful events because, in addition to the information above, some data may be missing, which makes the results less reliable.
We are not confident in the evidence from the studies where participants were not randomly placed into groups; the numbers of participants were also small.
Chemotherapy through an artery and vein compared to through an artery
We have little confidence in the evidence for saving the eye from being removed or survival, because participants were not randomly placed into groups. We are not confident in the evidence for the other outcomes for the same reason. Additionally, the studies defined and reported the outcomes differently and there were different follow-up times between groups.
How up to date is the evidence?
Our evidence is up to date to 10 September 2025.
Read the full abstract
Intra-arterial chemotherapy (IAC), intravenous chemotherapy (IVC), and the combination of both (IVC + IAC) are among the most important treatment options for retinoblastoma, a rare form of childhood cancer. The outcomes of previous studies evaluating the success rates of these methods have been discrepant due to the varying quality of the research as well as the different study types, sample sizes, and definitions of outcomes.
Objectives
To assess the benefits and harms of IAC, IVC, and the combination of both, in people with retinoblastoma.
Search strategy
We searched CENTRAL, MEDLINE, and Embase in September 2025. No search filters or restrictions regarding language or year of publication were used.
Selection criteria
We included randomized controlled trials (RCTs) and non-randomized studies of interventions (NRSIs) comparing either first-line IAC versus IVC or IVC + IAC versus IAC in children and adults with a confirmed diagnosis of retinoblastoma, irrespective of disease severity, gender, or ethnicity.
Data collection and analysis
We followed standard Cochrane methodology. We assessed the certainty of the evidence using GRADE.
Our main outcomes were tumor control with the avoidance of enucleation or external beam radiation therapy (EBRT), globe salvage (overall), overall survival, secondary neoplasms, tumor recurrence, development of metastasis, and the number of grade 3 and grade 4 adverse events at the end of short-term (< 1 year), medium-term (< 3 years), and long-term (> 3 years) follow-up.
Main results
We included six studies, of which three compared IAC with IVC (one RCT and two NRSIs) in 210 participants and 214 eyes. The other three studies compared IVC + IAC with IAC (three NRSIs) in 599 participants and 681 eyes. All participants in the included studies were children. The main results presented refer to a medium-term follow-up (up to three years).
IAC versus IVC
Findings of the RCT
IAC compared to IVC probably increases globe salvage (overall) (hazard ratio (HR) 2.01, 95% confidence interval (CI) 1.17 to 3.45; IVC: 260 per 1000; IAC: 454 per 1000 (95% CI 297 to 646/1000); 1 RCT, 143 eyes; moderate-certainty evidence). IAC compared to IVC probably results in little to no difference in overall survival (HR 0.97, 95% CI 0.20 to 4.80; IVC: 950 per 1000; IAC: 951 per 1000 (95% CI 769 to 989/1000); 1 RCT, 143 eyes; moderate-certainty evidence). IAC compared to IVC may result in little to no difference in tumor recurrence (RR 0.91, 95% CI 0.45 to 1.86; IVC: 180 per 1000; IAC: 164 per 1000 (95% CI 81 to 335/1000); 1 RCT, 143 eyes; low-certainty evidence). IAC compared to IVC may result in little to no difference in the number of grade 3 and grade 4 adverse events (1 RCT, 143 eyes; low-certainty evidence). Limitations of the evidence are a high risk of bias and serious imprecision. No other prioritized endpoints were reported in the RCT.
Findings of the NRSI
The evidence is very uncertain about the effect of IAC compared to IVC on tumor control with avoidance of enucleation or EBRT (1 NRSI, 23 eyes; very low-certainty evidence). Secondary neoplasms were not reported. IAC compared to IVC may have little to no effect on the development of metastasis, but the evidence is very uncertain (1 NRSI, 19 participants; very low-certainty evidence). Limitations of the evidence are an assessment of serious risk of bias and serious imprecision. Additional outcomes are shown in the results section.
IVC + IAC versus IAC
IVC + IAC compared to IAC may have little to no effect on tumor control with the avoidance of enucleation or EBRT, but the evidence is very uncertain (1 NRSI, 98 eyes; very low-certainty evidence). IVC + IAC compared to IAC may result in little to no difference in globe salvage (overall) (RR 0.96, 95% CI 0.89 to 1.03; IAC: 791 per 1000; IVC + IAC: 758 per 1000 (95% CI 703 to 814/1000); 3 NRSIs, 681 eyes; low-certainty evidence). IVC + IAC compared to IAC may result in little to no difference in overall survival (RR 1.02, 95% CI 0.98 to 1.07; IAC: 925 per 1000; IVC + IAC: 944 per 1000 (95% CI 904 to 990/1000); 3 NRSIs, 599 participants; low-certainty evidence). Secondary neoplasms were not reported. The evidence is very uncertain about the effect of IVC + IAC compared to IAC on tumor recurrence (3 NRSIs, 681 eyes; very low-certainty evidence) and on the development of metastasis (3 NRSIs, 599 participants; very low-certainty evidence). The evidence is very uncertain about the effect of IVC + IAC compared to IAC on the number of grade 3 and grade 4 adverse events (2 NRSIs, 386 participants; very low-certainty evidence). Limitations of the evidence are an assessment of serious risk of bias, serious inconsistency, and serious imprecision. Additional outcomes are shown in the results section.
Authors' conclusions
Due to the lack of randomized studies comparing first-line IAC with IVC and first-line IVC + IAC with IAC, most of the included studies are not masked (blinded) and are retrospective in design, which may lead to bias.
IAC versus IVC
IAC compared to IVC probably increases globe salvage (overall), probably results in little to no difference in overall survival, may result in little to no difference in tumor recurrence, and may result in little to no difference in the number of grade 3 and grade 4 adverse events.
IVC + IAC versus IAC
IVC + IAC compared to IAC may result in little to no difference in globe salvage (overall) and may result in little to no difference in overall survival.
Overall
Currently, there are mostly only retrospective, non-randomized studies on this topic with only a few randomized studies. More randomized studies with a higher number of study participants and comparable long-term results are needed to be able to determine the effect of IAC compared to IVC, or IVC + IAC compared to IAC, in people with retinoblastoma. There is an urgent need to develop a standardized and internationally valid nomenclature of endpoints to achieve greater homogeneity and clearer, comparable results.
