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Kilic et al1 reported in the October 2005 issue of the Archives that preenucleation radiotherapy (PER) improved long-term survival of patients with uveal melanoma.
In their prospective study, 167 Dutch patients with uveal melanoma received 8-Gy PER in 2 fractions 2 days before enucleation in 1978 and 1992 (to convert gray to rad, multiply by 100).1 A historical control group of 108 patients was treated by enucleation only (EO) in 1971 to 1992. Mean follow-up was 9.50 years in the PER group and 9.25 years in the EO group. No significant differences were observed in sex, tumor location, largest tumor diameter, cell type, and extrascleral growth between the 2 groups.
Survival after 4 years of follow-up was better in the PER group.1 The effect did not occur prior to 4 years of follow-up and it was more evident in the 15-year all-cause survival rates (47.5% in the PER group vs 25.2% in the EO group, a difference of 22.3 percentage points in favor of PER) than in the melanoma-related rates (63.7% in the PER group vs 51.0% in the EO group, a difference of 12.7 percentage points in favor of PER).
The larger, randomized Collaborative Ocular Melanoma Study2 of PER in which patients have been followed up for a mean time of at least 8.5 years did not show a similar survival difference overall or after 4 years of follow-up. It is useful to try to identify design factors in addition to randomization that may have contributed to the contradicting outcomes.
A difference in age was observed between the 2 groups in the Dutch study (mean age, 62.5 years in the EO group and 57.6 years in the PER group; P = .006).1 Kilic and colleagues acknowledged that older age could decrease survival in the EO group, but they found that the survival difference was present when adjusting for the age difference with Cox proportional hazards regression.
The age difference indeed may bias the results in favor of PER. Kilic and colleagues censored from Kaplan-Meier analysis patients who died of causes other than metastatic melanoma. The Kaplan-Meier estimate is calculated assuming that all of the censored patients remain at risk for the event of interest,3 which is the case if patients are lost to follow-up or survive until the study is terminated but not if they die of intercurrent disease. Censoring patients who are no longer at risk for melanoma death will produce Kaplan-Meier estimates of melanoma-related mortality that are highly biased. The bias is greater with longer follow-up and when competing causes of death are more frequent, in this case in the EO group in the study by Kilic and colleagues. The survival proportions in the Dutch study are more reliably estimated with cumulative incidence analysis, a method that is designed to analyze survival in the face of competing causes of death.4
The bias cannot be efficiently controlled for by Cox regression because this method likewise is based on the assumption that all of the patients remain at risk after they are censored from the analysis. Age may appear to be a predictor of melanoma-related mortality when Cox regression is applied but not necessarily if the same data set is analyzed by competing risks regression,5 a type of proportional hazards analysis that takes competing causes of death into account.6
We believe that a reanalysis of the data of Kilic and colleagues with cumulative incidence analysis and competing risks regression would be worthwhile. Parenthetically, in the Collaborative Ocular Melanoma Study, Kaplan-Meier estimates of melanoma-related mortality are also higher than cumulative incidence estimates, but randomization will have balanced competing causes of death between the 2 groups.2
Correspondence: Dr Kivelä, Ocular Oncology Service, Department of Ophthalmology, Helsinki University Central Hospital, Haartmaninkatu 4 C, PL 220, FI-00029 HUS Helsinki, Finland (tero.kivela@helsinki.fi).
Financial Disclosure: None reported.
Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature
Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal
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