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.

Manifest refraction versus autorefraction for patients with subfoveal choroidal neovascularization.

PURPOSE: To compare the results from manifest refraction using trial lenses and a standard visual acuity protocol to results from autorefraction for obtaining refractive error and best corrected visual acuity in patients enrolled in a randomized clinical trial. METHODS: During a 4-month period, 29 patients with subfoveal choroidal neovascularization (CNV), who were enrolled in the Submacular Surgery Trials (SSTs) Pilot Study at the Wilmer Ophthalmological Institute, gave verbal consent to participate in this study. Best corrected visual acuity was obtained using Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity charts and standardized room lighting after performance of manifest refraction, according to the SST protocol, and autorefraction. Refractive error (spherical equivalent) and visual acuity scores were obtained in both eyes of all patients. RESULTS: On average, manifest refraction gave a spherical equivalent that was 1.04 D more plus than autorefraction (95% limits of agreement = 0.74, 1.34). On average, the visual acuity score was 1.5 letters better after manifest refraction than after autorefraction (95% limits of agreement = 0, 3.0). The comparison of the two methods of refraction was subdivided according to visual acuity level and eye disease (age-related macular degeneration or ocular histoplasmosis syndrome). CONCLUSIONS: Despite large differences in spherical equivalent between manifest refraction and autorefraction, the visual acuity scores were close (mean difference, 1.5 letters). Other studies comparing subjective refraction and autorefraction have shown similar results. Autorefraction in patients with subfoveal CNV may be a satisfactory alternative to manifest refraction in clinical trials and field studies in which best corrected visual acuity is of interest.

Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: I. Ophthalmic outcomes submacular surgery trials pilot study report number 1.

PURPOSE: To report complications and changes in vision during 2 years of follow-up of patients with age-related macular degeneration assigned randomly to surgical removal or to laser photocoagulation of subfoveal recurrent neovascular lesions in a pilot trial designed to test methods, to refine estimates of outcome rates, and to project patient accrual rates for a larger multicenter randomized trial to evaluate submacular surgery. PATIENTS AND METHODS: Eligible patients with previous laser photocoagulation of extrafoveal or juxtafoveal choroidal neovascularization secondary to age-related macular degeneration were enrolled at 15 collaborating clinical centers. Assignments to treatment arm were made by personnel at a central coordinating center. Adherence to eligibility criteria and treatment assignment was assessed centrally at a photograph reading center. Patients were examined at 3, 6, 12, and 24 months after treatment for data collection purposes. Outcome measures reported include treatment complications, adverse events, requirements for additional treatment, and 2-year changes in visual acuity from baseline. RESULTS: Of 70 patients enrolled, 36 were assigned to laser photocoagulation and 34 to submacular surgery; all were treated as assigned. One patient in each group died before the 2-year examination. Visual acuity was measured at the 2-year examination for 31 of the surviving patients (89%) in the laser arm and for 28 of the surviving patients (85%) in the surgery arm. The 2-year measurements for 36 of the 59 patients (61%) were made by an examiner masked to treatment assignment and to the identity of the study eye. Improvements and losses of visual acuity were observed in both treatment arms; 20 of 31 study eyes (65%) in the laser arm and 14 of 28 study eyes (50%) in the surgery arm had visual acuity 2 years after enrollment that was better than or no more than 1 line worse than the baseline level. Changes in visual acuity and the size of the central macular lesions from baseline to the 2-year examination were similar in the treatment arms. Few serious complications were observed in either arm at the time of initial treatment; serious adverse events were rare. During follow-up, 11 laser-treated eyes and 18 surgically treated eyes had additional intraocular procedures. CONCLUSIONS: The data from this pilot trial suggest no reason to prefer submacular surgery over laser photocoagulation for treatment of patients with age-related macular degeneration who have lesions similar to those studied in this pilot trial. Any clinical trial designed to compare submacular surgery with laser photocoagulation in eyes with age-related macular degeneration and subfoveal recurrent neovascular lesions must enroll several hundred patients in order to reach a statistically valid conclusion regarding differences between these two methods of treatment with respect to either changes in visual acuity or complication rates.

Epidemiology of age-related macular degeneration.

For more than two decades, researchers have sought to identify "risk factors" for age-related macular degeneration (AMD), a major cause of irreversible vision loss in the Western world, particularly in the elderly. Two issues have complicated this search: failure to differentiate between different stages of AMD and misinterpretation of measures of association (odds ratios) and risk (risk ratios) derivable from different research designs. Fortunately, in more recent epidemiologic studies, more attention has been given to these issues. Three groups of potential "risk factors" that have been studied were reviewed: those known to be risk factors for cardiovascular disease, environmental factors, and racial and ethnic factors. Of these, only tobacco smoking, a known risk factor for cardiovascular disease, has been demonstrated to be associated with AMD consistently across many studies of different design, carried out within different populations. The available evidence supports at least a doubling of risk of late AMD associated with long-term smoking, a factor that is under the control of the individual. The preponderance of evidence has not supported other factors to the same degree. Presently, racial and ethnic factors are high priorities for further research.

Feasibility of keying data from screen-displayed facsimile images in an ongoing trial: the collaborative ocular melanoma study.

As part of an ongoing clinical trial, we conducted an experiment to assess the feasibility and to determine the reliability of data entry from a computer screen display of images of data collection forms transmitted by facsimile (fax) machines directly into a computer for paper forms designed without consideration of fax or image display requirements. Feasibility was assessed on the basis of accuracy and reliability of data entry and on operator satisfaction. During a 2-week period, half of the forms received at the Collaborative Ocular Melanoma Study (COMS) coordinating center were key-entered twice, using the paper forms as the source (paper source entry). The remaining forms were entered once using paper source and were later reentered using the screen display of images of the faxed forms as the source (image source entry). The latter group of forms, or 50% of all forms received, were entered a third time, using the image source entry. Two data entry operators participated in the experiment. Discrepancy rates between and within data entry operators were calculated for both modes of entry. A total of 50,861 keystrokes (28,095 items) across 1122 records were checked for consistency. The overall discrepancy rate associated with double paper source entry was approximately 21 per 10,000 keystrokes (20 per 10,000 items). Discrepancy rates associated with paper source versus image source entry (53 per 10,000 keystrokes [57 per 10,000 items]) and double image source entry (57 per 10,000 keystrokes [47 per 10,000 items]) were similar in magnitude. Image source entry of forms received by facsimile may provide an acceptable alternative to paper entry in ongoing multicenter clinical trials where the costs of converting existing forms and systems to automated data capture may be unacceptable. This experiment confirmed the feasibility of such an alternative and suggested that improved screen displays and changes in equipment to facilitate entry of data from the screen display may enhance accuracy of entries.

Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity.

PURPOSE: Geographic atrophy (GA) may cause significant compromise of visual function, even when there still is good visual acuity (VA), because of parafoveal scotomas and foveal function abnormalities antedating visible atrophy. This study evaluates the visual function abnormalities at baseline and the 2-year worsening of VA and reading rate for eyes with GA compared with a group of eyes with drusen only. METHODS: Seventy-four eyes with GA and VA greater than or equal to 20/50 from a prospective natural history study of GA were included, as were 13 eyes with only drusen. Baseline visual function testing and 2-year VA and maximum reading rate are reported. RESULTS: The worsening of VA in decreased luminance and foveal dark-adapted sensitivity showed severe abnormalities for the GA group. Contrast sensitivity was significantly reduced for the eyes with GA. Half the eyes with GA, but none of the drusen eyes, had maximum reading rates below 100 words per minute. A scanning laser ophthalmoscope (SLO) measure of the scotoma near fixation combined with a measure of residual foveal function accounted for 54% of the variability in maximum reading rate in the eyes with GA. Of 40 eyes with GA observed for 2 years, half lost greater than or equal to 3 lines of VA and one quarter lost greater than or equal to 6 lines. The nine eyes with drusen with follow-up had no significant change in VA. Low foveal dark-adapted sensitivity, SLO measures of the scotoma within 1 degree of fixation, and low maximum reading rate were statistically significant risk factors for doubling of the visual angle. Significant reduction in maximum reading rates at 2 years was present for the eyes with GA. CONCLUSIONS: The eyes with GA with good VA have profound decreases in visual function, particularly in dim lighting and in reading. Half the eyes with GA had doubling in visual angle at 2 years after the baseline examination, whereas the drusen eyes remained essentially unchanged. Impaired visual function at baseline was predictive of an adverse outcome for the eyes with GA.

Natural history of subfoveal subretinal hemorrhage in age-related macular degeneration.

PURPOSE: The authors describe the natural history of subfoveal subretinal hemorrhage (for which laser treatment was not indicated) in age-related macular degeneration. METHODS: A retrospective review of data was performed at a tertiary retinal referral center for 41 eyes from 40 patients with age-related macular degeneration examined during an 18-month period. All patients had at least 3 months of follow-up, as well as subfoveal subretinal hemorrhage that made up more than 50% of a neovascular lesion-as documented by fluorescein angiography-and therefore, did not meet criteria for laser treatment. The number of lines of visual acuity lost or gained in each eye during follow-up was calculated; presenting characteristics were evaluated as predictors of visual outcome. RESULTS: A progressive loss of visual acuity from baseline was observed throughout the 3-year follow-up period in most eyes. At 36 months, a mean of 3.5 lines of visual acuity had been lost in the 16 eyes examined; 44% of eyes had lost 6 or more lines of visual acuity. The percentage of patients who sustained a spontaneous improvement of 3 or more lines of visual acuity decreased from 31% at 12 months to 21% at 36 months of follow-up. Univariate linear regression analysis demonstrated significant relationships of initial size of the hemorrhage, elevation of the retina by the hemorrhage, and size of the entire lesion with visual outcome at the 12-month and 36-month examinations (P < 0.05). CONCLUSIONS: Although this study confirms that some eyes with subfoveal subretinal hemorrhage associated with age-related macular degeneration have poor prognoses, the visual acuity of other eyes did not deteriorate. These findings underscore the importance of evaluating the role of therapeutic interventions such as surgery to remove subretinal hemorrhage in randomized clinical trials.

Reliability of visual acuity measurements and screening under field conditions.

PURPOSE: The purpose of this analysis was to investigate the reliability of visual acuity screening and measurements made under field conditions when standardization of all test conditions is not possible. SETTING AND METHODS: In the Washington County Follow-Up Eye Study conducted in 1985 among cases of ocular histoplasmosis and controls from the same community who had been selected in 1970, a primary goal was to obtain a current visual acuity measurement of each eye of each participant in order to assess 15-year changes in visual acuity. Both visual acuity screening and measurement were accomplished on two separate occasions and in two separate locations (home or workplace and clinic) for 308 eyes and 317 eyes, respectively, of 161 participants. Screening was used to classify the visual acuity as 20/40 or better, worse than 20/40 but at least 20/160, or worse than 20/160. Screening and measurement were accomplished on at least one occasion for the eyes of 192 of 216 eligible individuals. RESULTS: Among 308 eyes screened twice, 289 (94%) were classified identically (kappa = 0.80). Among 317 eyes with visual acuity measured on two occasions, the measurements were within two lines for 305 eyes (96%; kappa = 0.50). Among eyes for which classifications of visual acuity from screening and measurement could be compared, 325 (96%) of 340 assessed at home and 326 (96%) of 338 assessed in clinic were classified in the same way (kappa = 0.86 and 0.88, respectively). CONCLUSION: Despite the unavoidable lack of standardization of test conditions when visual acuity was screened and measured in the home or work-place, the results were highly reliable when compared with visual acuity testing in the clinic under standard conditions.

Publications from multicentre clinical trials: statistical techniques and accessibility to the reader.

Articles from multicentre randomized clinical trials were analysed by methods adapted from Emerson and Colditz and Juzych et al. to compare the frequency with which different statistical methods are used by clinical trials investigators with the frequency used by other researchers, and to determine how much statistical knowledge is required to interpret the statistical treatment of data from clinical trials. We observed differences between the frequency of usage of statistical methods and the accessibility of the clinical trials publications and those of all medical research articles published by specific journals. Clinical trials publications are less accessible than others in medical journals to the reader who knows only descriptive statistics, t-tests, contingency tables, power calculations, and life table methods. Many more statistical methods must be known by a reader to understand fully publications regarding treatment group comparisons for the primary outcomes of interest from clinical trials.

Risk of visual impairment attributable to ocular histoplasmosis. Washington County Follow-up Eye Study Group.

PURPOSE: To compare 15-year incidence rates of visual impairment and vision-threatening conditions between cases with ocular histoplasmosis and controls residing in the same endemic community. METHODS: Controls and cases with and without disciform lesions who were between 30 and 69 years of age when selected, interviewed, and examined in 1970 were reinterviewed and reexamined in 1985. RESULTS: Of the 252 cases and controls examined in 1970, 216 were still alive in 1985. Of these, 202 (94%) were interviewed; 197 (91%) underwent visual acuity measurement; and 173 (80%) were examined by a study ophthalmologist. Both in 1970 and in 1985, cases with disciform macular lesions of ocular histoplasmosis had a higher prevalence of both unilateral and bilateral visual impairment and blindness. Although prevalence of visual impairment and blindness in 1985 was similar among controls and cases of ocular histoplasmosis without disciform lesions, this group of cases had about twice the incidence of visual impairment as that of controls. However, the 95% confidence intervals on estimates of relative risks were broad and included unity. No new disciform lesions attributable to ocular histoplasmosis were found in 28 eyes of 18 cases free of them in 1970 or among 148 controls. CONCLUSIONS: The 15-year risk of visual impairment and blindness appears to be somewhat higher among adults aged 30 years and older who have only peripheral atrophic scars characteristic of ocular histoplasmosis than among individuals without such scars who live in the same endemic community. Adults who already have a disciform lesion attributed to ocular histoplasmosis in one eye are at low risk of development of a disciform lesion in the fellow eye later in life.

A review of mortality from choroidal melanoma. I. Quality of published reports, 1966 through 1988.

The literature concerning mortality after a diagnosis of choroidal melanoma was reviewed to identify relevant articles published from 1966 through 1988 and to select those with mortality rates presented separately by tumor size for inclusion in a pooled analysis (meta-analysis) of 5-year mortality after enucleation for choroidal melanoma. The quality of the published literature for our purposes was assessed. Candidate articles were identified from a search of the MEDLINE files by an information specialist. Altogether, of 217 candidate articles, 76 (70 from the MEDLINE search and six more from our files) qualified for review. All-cause mortality rates were reported in 80% of the articles. Among six aspects of design and methods for which information was sought, eligibility criteria were reported in 52 (68%) of the 76 articles and statistical methods were cited in 38 (50%); other information was reported with intermediate frequency. Quality scores based on completeness of reporting with respect to 16 factors ranged from 13.3 to 92.3 of a possible 100.0. Findings suggest that researchers, clinicians, journal editors, and reviewers should be more attentive to the completeness of reports from clinical research studies with respect to basic information regarding design and methods.

A review of mortality from choroidal melanoma. II. A meta-analysis of 5-year mortality rates following enucleation, 1966 through 1988.

With the use of data published during the period from 1966 through 1988, a pooled analysis (meta-analysis) of 5-year mortality rates among patients who had an eye enucleated for choroidal melanoma was performed to provide a more robust estimate of this rate than could be obtained from any single study. The literature concerning mortality following a diagnosis of choroidal melanoma has been reviewed systematically and described in a separate article. Of 76 reports published from 1966 through 1988, 29 were excluded from the meta-analysis because there were no cases treated by enucleation alone, mortality was not reported by time from enucleation, fewer than 10 cases were reported, or 5-year mortality rates were not reported or derivable from the data presented. Ten additional reports were excluded because they were based on data for the same set of patients as another article in the series. Of the remaining 37 reports, 29 contained data for patients with tumors of varying sizes that could not be separated into subgroups based on the size of the tumor at the time of treatment. The remaining eight articles reported 5-year mortality rates by tumor size, specifically for small, medium, or large tumors. The combined weighted estimates of 5-year mortality rates following enucleation were 16% for small tumors (95% confidence interval [CI]: [14%, 18%]), 32% for medium tumors (95% CI: [29%, 34%]), and 53% for large tumors (95% CI: [50%, 56%]). Different methods of pooling the data yielded consistent estimates for all three tumor size categories.(ABSTRACT TRUNCATED AT 250 WORDS)

Patient and clinic factors predictive of missed visits and inactive status in a multicenter clinical trial. The Macular Photocoagulation Study Group.

Obtaining complete patient follow-up in clinical trials is important for the analysis of treatment results and for good patient care. Incomplete data can introduce bias into study results and can alter conclusions concerning treatment efficacy. The purpose of this study was to explore in a case-control design patient and clinic factors that may be associated with missed visits or inactive status within three clinical trials conducted as part of the Macular Photocoagulation Study. All inactive patients, all patients with any missed visits, and a random sample of patients with no missed visits were selected for interview. A total of 175 patients (60% of 292 selected) participated in the study. Two factors were found to be significantly associated (P less than .05) both with inactive status and with having any missed visits: health problems and travel costs. Several patient and clinic factors were found to be associated only with inactive status. These included change in marital status since joining the study, retirement since study entry, unsatisfactory interactions with the study physician or clinic coordinator, too little time spent with the study physician, and patient's belief that participants should be paid to participate in clinical trials. Distance from the clinic greater than 100 miles, in addition to health problems any time during follow-up and problems with travel costs, was found to be associated only with having any missed visits. This study emphasizes the importance of maintaining good patient-staff interactions and sensitivity to the events in a patient's life in order to obtain complete patient follow-up.

Data monitoring committees for multicenter clinical trials sponsored by the National Institutes of Health. I. Roles and membership of data monitoring committees for trials sponsored by the National Eye Institute.

The operational aspects of data monitoring committees for multicenter clinical trials have received little attention in the published literature, in contrast to a wealth of publications concerning the statistical aspects of data monitoring. Occasional anecdotal reports suggest that the role of these committees is complex and that responsibilities and decisions extend beyond choice of a stopping rule. In an effort to gain a better appreciation of the domain of responsibilities shared by all or most of the data monitoring committees (DMCs) for the 20 multicenter studies (30 clinical trials) sponsored by the National Eye Institute, one of the National Institutes of Health, published information was studied and key members of the DMCs for these studies were surveyed. Information about the membership of these important groups also was sought in order to guide those with responsibility for appointing future DMCs. Three tasks--all directly associated with monitoring accumulating data for evidence of benefit or harm to trial patients--were reported unanimously to be the responsibility of the DMCs. In addition, many responsibilities concerned with study oversight rather than data monitoring were assigned to the DMC in 75% or more of the trials. The domain of responsibilities common to a majority of the DMCs suggests that these groups function in most NEI-sponsored multicenter trials as combined data monitoring and policy boards, even when not so designated. The median size of the 20 DMCs was 10 members, with six appointed and four ex officio members. Ophthalmologists accounted for 38% of all DMC positions and statisticians for 33%.