The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, II: characteristics of patients enrolled and not enrolled. COMS Report No. 17.

OBJECTIVES: To describe characteristics of patients evaluated for the Collaborative Ocular Melanoma Study (COMS) randomized clinical trial of iodine 125 brachytherapy for choroidal melanoma by enrollment status, and to compare characteristics of patients enrolled with those of patients with tumors of eligible size who did not enroll in order to assess the extent to which findings from the clinical trial can be generalized to future patients. METHODS: For all patients diagnosed with choroidal melanoma and evaluated for the clinical trial at COMS centers from November 1986 through July 31, 1998, selected data were transmitted to the COMS Coordinating Center, Baltimore, Md, where they were integrated and analyzed. Data included ophthalmic and medical history, examination findings, and visual acuity measurements recorded prior to enrollment; standardized A- and B-scan echographic examination findings; and wide-angle fundus photographs and fluorescein angiograms. RESULTS: Of 8712 patients with choroidal melanoma, 5046 had tumors of eligible size; of these, 2882 (57%) were eligible for enrollment, and 1317 (46% of eligible patients, 26% of patients with tumors of eligible size) enrolled. Most differences between eligible and ineligible patients corresponded to eligibility and exclusion criteria. However, ineligible patients were older and had thicker tumors than eligible patients. Eligible patients who enrolled were slightly older and had larger tumors than those who did not enroll. Nearly half (48%) of enrolled patients had choroidal melanoma with the apex located temporal to the fovea, compared with 40% of eligible patients not enrolled and 29% of ineligible patients. CONCLUSIONS: This trial was designed to yield internally valid treatment comparisons through random assignment to treatment at time of enrollment. Information from this and other studies document that enrolled patients were similar to other patients with choroidal melanoma who were treated with 125I brachytherapy. These findings support the external validity of the trial and applicability of treatment findings to all patients who meet the criteria used to judge eligibility for the trial.

The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, III: initial mortality findings. COMS Report No. 18.

OBJECTIVES: To report initial mortality findings from the Collaborative Ocular Melanoma Study (COMS) randomized clinical trial of iodine 125 brachytherapy vs enucleation for treatment of choroidal melanoma. METHODS: Patients were evaluated for eligibility at 43 participating clinical centers in the United States and Canada. Eligible consenting patients were assigned randomly at the time of enrollment to enucleation or 125I brachytherapy. Patients were examined at specified intervals after enrollment for data collection purposes. Findings presented herein are based on data received by September 30, 2000. Data for each patient were analyzed with the treatment group to which the patient was assigned randomly at the time of enrollment. RESULTS: During the 11(1/2)-year accrual period, 1317 patients enrolled; 660 were assigned randomly to enucleation and 657 to 125I brachytherapy. Only 2 patients in the enucleation arm were found to have been misdiagnosed when histopathology was reviewed centrally. All but 17 patients (1.3%) received the assigned treatment. Adherence to the brachytherapy protocol was excellent, with 91% of patients treated per protocol. Based on time since enrollment, 1072 patients (81%) had been followed for mortality for 5 years and 416 (32%) for 10 years. A total of 364 patients had died: 188 (28%) of 660 patients in the enucleation arm and 176 (27%) of 657 patients in the brachytherapy arm. The unadjusted estimated 5-year survival rates were 81% and 82%, respectively; there was no clinically or statistically significant difference in survival rates overall (P =.48, log-rank test). The adjusted estimated risk ratio for 125I brachytherapy vs enucleation was 0.99 (95% confidence interval [CI], 0.80-1.22). Five-year rates of death with histopathologically confirmed melanoma metastasis were 11% and 9% following enucleation and brachytherapy, respectively; after adjustment, the estimated risk ratio was 0.91 (95% CI, 0.66-1.24). CONCLUSIONS: Mortality rates following 125I brachytherapy did not differ from mortality rates following enucleation for up to 12 years after treatment of patients with choroidal melanoma who enrolled in this COMS trial. The power of the study was sufficient to indicate that neither treatment is likely to increase or decrease mortality rates by as much as 25% relative to the other.

Collaborative ocular melanoma study (COMS) randomized trial of I-125 brachytherapy for medium choroidal melanoma. I. Visual acuity after 3 years COMS report no. 16.

OBJECTIVE: To report visual acuity during the first three years after iodine 125 (I(125)) brachytherapy for medium-sized choroidal melanoma and to identify important baseline and treatment factors associated with posttreatment visual acuity in a group of patients who were treated and observed prospectively as part of a large, randomized clinical trial. DESIGN: Observational case series within a randomized, multicenter study. PARTICIPANTS: Patients enrolled in the Collaborative Ocular Melanoma Study randomized trial of I(125) brachytherapy versus enucleation had choroidal melanoma of at least 2.5 mm but no more than 10.0 mm in apical height, and no more than 16.0 mm in largest basal dimension. One thousand three hundred seventeen patients enrolled from February 1987 through July 1998; 657 patients were assigned to I(125) brachytherapy. Visual acuity data for 623 patients who received I(125) brachytherapy as randomly assigned and who have been observed for at least 1 year were analyzed for this report. METHODS: Under study protocol, an ophthalmic evaluation, including best-corrected visual acuity measurement of each eye, was performed at baseline, every 6 months thereafter for 5 years, and once yearly thereafter. Two poor vision outcomes, visual acuity of 20/200 or worse that was confirmed at the next follow-up examination and loss of six lines or more of visual acuity from baseline that was confirmed at the next follow-up examination, were analyzed to identify baseline and treatment characteristics that were associated with posttreatment visual acuity. RESULTS: At baseline, median visual acuity in the eye with choroidal melanoma was 20/32, with 70% of eyes having 20/40 or better and 10% of eyes having 20/200 or worse visual acuity. Three years after I(125) brachytherapy, median visual acuity was 20/125, with 34% having 20/40 or better and 45% having 20/200 or worse visual acuity, including eyes that were enucleated within 3 years of treatment. Life-table estimates of percentages of patients who lost six or more lines of visual acuity from baseline, a quadrupling of the minimum angle of resolution, with this finding confirmed at the next 6-month follow-up examination, were 18% by 1 year, 34% by 2 years, and 49% by 3 years after treatment. Life-table estimates of percentages of patients with baseline visual acuity better than 20/200 whose visual acuity decreased to 20/200 or worse, confirmed at the next follow-up examination, were 17% by 1 year, 33% by 2 years, and 43% by 3 years after treatment. As soon as a poor vision outcome was observed, improvement of visual acuity to a level that no longer met the definition for a poor vision outcome was rare. Greater baseline tumor apical height and shorter distance between the tumor and the foveal avascular zone (FAZ) were the factors most strongly associated with loss of six or more lines of visual acuity after treatment. These two factors and baseline visual acuity also were strongly associated with visual acuity 20/200 or worse after treatment. Patient history of diabetes, presence of tumor-associated retinal detachment, and tumors that were not dome shaped also were associated with greater risk for both of the poor vision outcomes. CONCLUSIONS: Forty-three percent to 49% of treated eyes had substantial impairment in visual acuity by 3 years after I(125) brachytherapy, defined as a loss of six or more lines of visual acuity from the pretreatment level (49% of eyes) or visual acuity of 20/200 or worse (43% of eyes) that was confirmed at the next 6-month examination. Patients with a history of diabetes and patients whose eyes had thicker tumors, tumors close to or beneath the FAZ, tumor-associated retinal detachment, or tumors that were not dome shaped were those most likely to have a poor visual acuity outcome within 3 years after I(125) brachytherapy.

Single-dose compared with fractionated-dose radiation of the OM431 choroidal melanoma cell line.

PURPOSE: To compare single-dose and fractionated-dose radiotherapeutic effects on choroidal melanoma cells. METHODS: We determined the effects of gamma radiation on OM431 cell survival by exposing cells to either a single 9-Gy dose or two 4.5-Gy fractionated doses at intervals of 20 minutes to eight hours. The effects of single dosing and fractionated dosing at six hours were compared at doses of 2 to 12 Gy. RESULTS: Tumor cell repair was most rapid during the first two hours. Maximum repair had occurred by six hours after radiation. Cell survival curves showed doses greater than 3 Gy of single-dose gamma radiation resulted in a greater number of cells killed than did equivalent fractionated doses. CONCLUSIONS: Ocular melanoma in vitro is relatively radioresistant to low-dose fractionated radiotherapy. High single-dose radiotherapy would be more effective but would also result in more damage to normal tissue unless more focused modalities of radiotherapy are used.

Effects of gamma radiation on the OM431 human ocular melanoma cell line.

In order to determine the dose responsiveness to radiation of ocular melanoma, we conducted an in vitro dose-response study on a monolayer cell culture using a clonogenic assay. The effects on cell survival were determined relative to unirradiated controls. A human epithelioid ocular melanoma cell line, OM431, was maintained in tissue culture and serial dilutions of viable cells were plated in flasks, allowed to settle and attach for 48 h, and subsequently irradiated with 1-10 Gy in single fractions. After 2 weeks, the number of reproducing clones (forming colonies with greater than 32 cells or five generations) were counted. The surviving fractions of cells were plotted on a cell survival curve using the linear quadratic model. The survival curve showed a large initial shoulder followed by an exponential decline in growth. Our data suggest that the OM431 ocular melanoma cell line responds to irradiation in a manner similar to other melanoma cell lines and is relatively radioresistant especially at lower doses.

Distribution and activity of glutathione-S-transferase in normal human lenses and in cataractous human epithelia.

The distribution of glutathione-S-transferase (GST) activity was determined in frozen normal human lenses. The highest activity of GST was found in the peripheral and equatorial regions, whereas the lowest activity was found in the nucleus. Western blot showed that both mu and pi isoenzymes of GST were present in human lenses. This result is similar to that found in rat lenses. In addition, GST activity was analyzed in 50 lens epithelia which were obtained during cataract surgery. Twenty-seven lens epithelia showed no activity. Statistically significant association was found between cortical and mixed cortical--nuclear cataract and loss of GST activity. No association was found between pure nuclear cataract and loss of epithelial GST activity.

Results of inpatient and outpatient cataract surgery. A historical cohort comparison.

PURPOSE: The transition from inpatient to outpatient cataract surgery during the last decade was not accompanied by prospective investigation of its effect on visual outcomes or surgical complications. The authors performed this study to assess the impact of this transition on surgical results. METHODS: The authors reviewed 600 extracapsular cataract extractions performed by 4 experienced ophthalmic surgeons during a 36-month period; in 300 cases, patients were hospitalized after surgery (inpatient group), and, in 300 cases, patients were never hospitalized (outpatient group). The same surgical techniques were used in all cases. Visual outcome and rates for operative and postoperative complications were compared. RESULTS: There were no statistically significant differences between the inpatient and outpatient groups for visual acuity. Excluding patients with pre-existing nonlenticular ocular disease, a best-corrected visual acuity of 20/40 or better was achieved in 93.1% of inpatient cases and in 97.2% of outpatient cases 6 months after surgery. Postoperative, clinically apparent cystoid macular edema was more common in the inpatient group (P = 0.03); however, after exclusion of patients with diabetes, hypertension, age younger than 65 years, and eyes with pre-existing nonlenticular disease, there was no statistically significant difference between groups. No significant differences in rates for other operative and postoperative complications were identified, including wound dehiscence, unplanned postoperative filtering blebs, infectious endophthalmitis, retinal detachment, persistent iridocyclitis, glaucoma, and corneal edema. CONCLUSION: This study does not demonstrate that the transition to outpatient cataract extractions has had an adverse effect on surgical outcomes.

Lens capsule and epithelium in age-related cataract.

On the basis of preoperative assessment of patient characteristics, intraoperative obtainment of a lens-capsule and epithelium specimen, histopathologic investigation of lens capsule and epithelium, and biochemical analysis of glutathione reductase in lens epithelium, age-related cataract was studied in 50 adult patients who underwent consecutive extracapsular cataract-posterior chamber lens implant surgery. Patients (25 men and 25 women; age range, 41 to 91 years; mean age, 75 years) had a wide range of systemic and ocular disease; 17 of 50 (34%) patients had a history of severe vision-impairing cataract in a first-degree relative. Anterior lens-capsule thickness ranged from 10 to 22 microns, with a mean of 17 microns. Statistical analysis of lens-epithelium ultrastructure in 41 of 50 specimens documented mixing of normal and abnormal cells, verified a gradation in the degree of abnormal ultrastructural features, and demonstrated a statistically significant decrease in epithelial cytologic activity with advancing age (P = .038). Biochemical analysis documented a severe glutathione reductase deficiency in nine of 39 (23%) lens-epithelium specimens, possibly reflecting a dietary deficiency of riboflavin.

Tissue plasminogen activator treatment of experimental subretinal hemorrhage.

To determine if tissue plasminogen activator, a clot-specific fibrinolytic agent, could eventually be used to assist in the clearance or removal of subretinal hemorrhage, we studied the effect of subretinal injections of tissue plasminogen activator, autologous blood, balanced salt solution, and the combination of either tissue plasminogen activator or balanced salt solution after subretinal injection of autologous blood on retinal morphologic characteristics and clearance of subretinal hemorrhage in the albino rabbit. No morphologic evidence of tissue plasminogen activator toxicity was found in the rabbit retina at a dose of 25 to 50 micrograms/0.1 ml. Subretinal hemorrhage cleared faster after subretinal injection of tissue plasminogen activator when compared to balanced salt solution (P = .0005) but did not completely prevent overlying retinal degeneration. Both tissue plasminogen activator and balanced salt solution were found to decrease the toxic effects of subretinal blood on the morphologic characteristics of the rabbit retina, and this effect can be explained at least partly by dilution of the subretinal blood.