Ординатура / Офтальмология / Английские материалы / Ocular Oncology_Albert, Polans_2003

clinical center and individual center participants, including the treating surgeon, following ophthalmologist, radiation oncologist and physicist, clinic coordinator, echographer, photographer, visual acuity examiner, and reviewing pathologist. Standardized forms were developed for patient demographics, initial patient evaluation, treatment documentation, echography, photography, and patient follow-up [6]. Patient mortality, including pathological review for metastatic disease, was standardized and National Death Index review was included within the trial design to maximize data collection for the primary study outcome of mortality [7]. All data were collated at the centralized coordinating center and reviewed by the external Data and Safety Monitoring Committee.

The COMS was structured to ensure standardization of patient entry, treatment, follow-up, and outcome assessment [2]. This study employed centralized units to coordinate studywide activities and included the Chairman’s Office, Coordinating Center, Echography Center, Pathology Center, Radiologic Physics Center, and Photograph Reading Center, along with the independent Data and Safety Monitoring Committee. Each study center maintained responsibility for oversight of patient eligibility, treatment, and study compliance. Individual patient data—including demographics, tumor characteristics, individual treatment parameters, and follow-up visits—were collated by the Coordinating Center. Baseline echograms and follow-up studies were evaluated for eligibility and tumor response by the Echography Center [3]. Enucleated globes and all biopsy tissues were reviewed within the Pathology Center. Treatment planning for eyes undergoing either fractionated external beam radiotherapy or iodine-125 brachytherapy was reviewed for compliance with standardized study treatment parameters at the Radiologic Physics Center [8]. Fundus photographs and fluorescein angiography were collated within the Photograph Reading Center. Overall study integration remained the responsibility of the Chairman’s Office, while individual study centers were directed by an on-site principal investigator. This study design is a classic example of a large, multicentered, randomized clinical trial and played a significant role in assuring excellent standardization and compliance. This study design was also associated with the significant study costs incurred by the COMS throughout its trial period.

The COMS trial arms were first funded in 1985 by the National Eye Institute and then jointly funded in 1991 by the National Eye Institute and the National Cancer Institute. The Small Tumor Observational Study accrued 204 patients between December 1986 and August 1989 [9,10]. Small choroidal melanomas were eligible for this study if the tumor was between 1.0 and 3.0 mm in apical height and 5.0–16.0 mm in largest basal dimension. Patients were evaluated for all-cause mortality, melanoma-related mortality, and factors predictive of tumor growth and/or tumor treatment. The medium tumor trial accrued 1317 patients between February 1987 and July 1998. Medium choroidal melanomas were eligible for this study if the tumor was between 2.5 to 10.0 mm in apical height (3.0–8.0 mm until November 1990) and 5.0–16.0 mm in largest basal dimension. Patients were evaluated for the primary outcome of all-cause mortality and secondary outcomes including melanoma-related mortality, local tumor control, treatment-related complications, visual acuity, and quality of life. The large tumor trial accrued 1003 patients between November 1986 and December 1994. Large choroidal melanomas were eligible for this study if the tumor was greater than 10 mm in apical height (greater than 8.0 mm until November 1990) or greater than 16.0 mm in largest

basal dimension. Patients were evaluated for the primary outcome of all-cause mortality and secondary outcomes including melanoma-related mortality, local tumor recurrence, orbital complications, or treatment-related complications.

The Small Tumor Observational Study focused on the outcome of studyeligible patients to determine the feasibility of a future randomized clinical trial [11]. A total of 204 patients with a median age of 62 years were followed for a median of 92 months. Of the 188 patients not treated immediately within the study, 46 exhibited local tumor growth within the follow-up window. Kaplan-Meier analysis of tumor growth documented a 21% 2-year and 31% 5-year incidence of tumor growth requiring definitive tumor treatment. Clinical factors predictive of tumor growth included greater initial tumor thickness and diameter, presence of orange pigment, absence of drusen and/or retinal pigment epithelial change, and presence of tumor pinpoint hyperfluorescence on angiography.

The Small Tumor Observational Study evaluated survival outcomes including all-cause mortality and melanoma-related mortality for all study participants. Kaplan-Meier analysis of 5-year all-cause mortality was 6%, and 8-year all-cause mortality was 14.9%. Kaplan-Meier analysis of melanoma-specific mortality was 1 and 3.7%, respectively, for 5 and 8 years. This study, though, suffers from the limitations of all nonrandomized reviews, including potentials for treatment bias, nonstandardized treatment, variability in follow-up, and absence of prospective data collection. Nonetheless, the Small Tumor Observational Study did establish data documenting the low mortality in patients participating within the framework of this observational study [11].

The Medium Choroidal Melanoma Trial evaluated 8712 patients during the study accrual window and noted 2882 patients who were eligible for study participation [12–15]. A total of 1317 patients with a mean age of 60 years participated in this clinical trial. Randomization between standardized enucleation and iodine-125 brachytherapy established overlapping treatment groups without evidence of clinically significant selection bias. Evaluation of eligible patients documented no clinically significant differences between patients enrolling and those not enrolling within the clinical trial, allowing for generalization of the study findings to patients eligible for the clinical trial [14].

Local treatment failure and enucleation were evaluated among the 657 patients assigned to iodine-125 brachytherapy [15]. Kaplan-Meier analysis of local tumor failure documented an incidence of 10.3% at 5 years posttreatment. Local treatment failure was the primary cause of enucleation within 3 years of treatment; while ocular pain without evidence of treatment failure was the most common cause of enucleation occurring more than 3 years from brachytherapy. Kaplan-Meier analysis of risk of enucleation by 5 years was 12.5%. Risk factors for treatment failure were older age at time of initial treatment, posterior tumor location, and greater tumor thickness; while risk factors for enucleation included greater tumor thickness, posterior tumor location, and poorer baseline visual acuity. Local tumor failure was weakly associated with reduced survival, with an adjusted risk ratio of 1.5 (Table 1).

Visual acuity was evaluated for patients undergoing standardized iodine-125 brachytherapy within the Medium Choroidal Melanoma Trial. Kaplan-Meier lifetable analysis evaluated two clinically significant outcomes at a 36-month window:

(1) decline of best-corrected visual acuity to 20/200 or worse and (2) loss of six lines

a Foveal avascular zone. Source: Ref. 15.

or more of visual acuity from baseline (a quadrupling of the visual angle) [12]. All enucleated patients were counted as having poor vision for the purpose of this analysis. Life-table analysis of the rate of decrease in visual acuity equal to or worse than 20/200 noted an incidence of 17% of patients by 1 year and increased to 43% of patients by 3 years. Loss of six or more lines of visual acuity occurred in 18% of patients by 1 year, 34% by 2 years, and in 49% by 3 years postbrachytherapy. Recovery of visual acuity was rare, occurring in less than 5% of patients. Overall, on average, patients experienced a decline in visual acuity of two lines per year after brachytherapy (Tables 2 and 3). Risk factors associated with loss of visual acuity included greater tumor thickness, posterior tumor location [including the foreal avascular zone (FAZ)], poorer baseline visual acuity, non-dome-shaped tumors, greater radiation treatment dose to the fovea/optic nerve/opposite eye wall, and systemic diabetes mellitus.

The primary study outcome within the COMS was all-cause mortality and secondarily histopathologically confirmed melanoma metastasis with death [13]. Of the 1317 enrolled patients, 660 were assigned to enucleation and 657 to iodine-125 brachytherapy. Central review of all enucleated specimens documented misdiagnosis in only 2 patients (2 of 660 patients, 0.003%) undergoing randomization to enucleation. Sample size analysis was selected with a power to detect a 25% difference in mortality based on selected treatment and determined a minimal sample size of 1250 randomized patients. Kaplan-Meier analysis was utilized to determine time-to-death estimates, while survival rates by treatment arm were analyzed using the log-rank test. At the time of data analysis for publication, 1072 patients (81%) had been followed for 5 years, while 416 patients (32%) had been followed for at least 10 years from study entry. Kaplan-Meier analysis of cumulative all-cause mortality at 5 years was 18% for iodine-125 brachytherapy and 19% for enucleation. KaplanMeier analysis of mortality with histopathologically confirmed metastases at 5 years were 9% after iodine-125 brachytherapy and 11% after enucleation (Figs. 1 and 2). No statistically significant difference was noted for either treatment outcome based on the selected treatment of iodine-125 brachytherapy or enucleation. Risk factors associated with mortality included greater apical tumor height, increased longest tumor basal diameter, posterior tumor location, and older patient age.

The Large Choroidal Melanoma Trial evaluated 1302 eligible patients and accrued 1003 patients between November 1986 and December 1994 into the multicentered clinical trial [13,16–19]. Patients were randomized to primary enucleation or to fractionated pre-enucleation external-beam radiotherapy, followed by standardized enucleation. Pre-enucleation fractionated external-beam radiotherapy was delivered in five daily 4.0-Gy fractions for a total delivered dose of 20 Gy. Standardized enucleation was performed within 4 weeks of study entry and within 80 hr of completion of radiotherapy.

Of the 1003 study patients (mean age of 60 years), 506 patients were randomized to standard enucleation and 497 to pre-enucleation radiotherapy followed by enucleation [18]. The two treatment arms were, again, well balanced, and tumors were noted to have a mean apical height of 9.5 mm and a mean longest basal diameter of 17.3 mm. Local treatment complications were evaluated in all patients undergoing enucleation surgery. Orbital tumor recurrence (biopsyconfirmed) occurred in no patients with pre-enucleation radiotherapy followed by enucleation compared with 5 patients with orbital tumor recurrence undergoing standardized enucleation alone ( p ¼ 0.03, Fisher exact test). Additionally, severe ptosis had a statistically significant lower incidence for patients undergoing preenucleation radiotherapy followed by enucleation compared with the randomized group undergoing enucleation alone ( p ¼ 0.007, log-rank test). At 5 years follow-up, the most common complication was poor prosthetic motility occurring in 18% of patients (not statistically significant). Pre-enucleation radiotherapy was not associated with increased postsurgical orbital or lid complications [18].

Histopathological review of eyes enucleated within the COMS Large and Medium Choroidal Melanoma trials was significant for the large standardized sample size (1527 globes) and centralized independent ocular pathological grading [8,20]. The accuracy of diagnosis confirmed by this review was high (99.7%), with five misdiagnosis, of which four globes contained metastatic adenocarcinoma and one contained a choroidal hemangioma. Mixed cell type was noted in 86% of eyes, with

only 5% of eyes containing primarily epithelioid cells. Local tumor invasion was significant, occurring in 81% of all study eyes. Extrascleral extension was present in 8% of eyes, while scleral invasion was noted in 56%. Retinal invasion and vitreous extension were present in 49 and 25% respectively. Mitotic activity was present in 9% of high-power fields in large choroidal tumors undergoing enucleation alone, in 5% of high-power fields in medium choroidal tumors undergoing enucleation, and in only 3% of high-power fields in eyes undergoing pre-enucleation radiotherapy followed by enucleation ( p ¼ 0.001). Increased intratumoral macrophage number was significantly associated with increased tumor pigmentation and increased tumor necrosis ( p ¼ 0.001 and p ¼ 0.01 respectively).

The primary study outcome within the COMS was all-cause mortality and, secondarily, histopathologically confirmed melanoma metastasis with death [17]. In the Large Choroidal Melanoma Trial, the sample-size analysis was selected with a 90% power to detect a 20% difference in mortality based on selected treatment; it determined an effective sample size of 1003 randomized patients. Kaplan-Meier analysis was utilized to determine time-to-death estimates while survival rates by treatment arm were analyzed using the log-rank test. At the time of data analysis for publication, 734 patients (73%) had been followed for 5 years, while vital status at 10 years was available for 589 patients (59%) from study entry. Kaplan-Meier analysis of cumulative all-cause mortality at 5 years was 38% for pre-enucleation radiotherapy followed by enucleation and 42% for patients undergoing enucleation alone ( p ¼ 0.32, log-rank test) (Figs. 3 and 4). Cox proportional hazards analysis notes an overall risk ratio of 0.91 for pre-enucleation radiation therapy followed by enucleation when compared with enucleation alone. Kaplan-Meier analyses of mortality with histopathologically confirmed metastases at 5 years were 26% after pre-enucleation radiotherapy followed by enucleation and 28% after enucleation alone. No statistically significant difference was noted for either treatment outcome based on the selected treatment of pre-enucleation radiotherapy followed by enucleation or enucleation alone. Metastatic involvement was again most commonly noted to involve the liver (93%). Risk factors associated with mortality included increased longest tumor basal diameter and older patient age at study entry (Tables 4 and 5).

Evaluation of patient demographics to determine differences between evaluated patients with choroidal melanoma who are eligible versus those patients with choroidal melanoma who are ineligible, along with the correlate evaluation of eligible patients who elected to participate in the COMS and those who elected to be treated outside of the COMS, is key in determining both internal and external study validity [21]. This evaluation allows the clinician to determine study bias external to the randomization process and is paramount in determining the overall ability to generalize study data to patients outside of the study. Patient characteristics were reported for the Medium and Large Choroidal Melanoma trials and excellent internal and presumptive external validity was documented. These demographic data represent the single largest series of patients reported within a standardized environment, incorporating data generated from all 43 centers in North America.

The COMS evaluated 8712 patients with choroidal melanoma during the Medium Choroidal Melanoma Trial accrual study window [12–15]. A total of 5046 patients had tumors of eligible size, while 2882 met all study criteria for entry; 1317

patients elected to participate (46% of all eligible patients, 26% of all-size eligible tumors). Eligible patients had a mean age of 59 years, an equal number of men and women were eligible and participated, and 98% of patients were non-Hispanic whites. Patients were evaluated at the COMS clinical center at a median of 9 days from initial diagnosis. Visual acuity was 20/20 in 35% of the eligible patients’ tumorcontaining eye (Table 6) [12]. Tumor characteristics noted a mean apical height of 4.8 mm and longest basal diameter of 11.4 mm. The posterior border of the tumor was noted to be a mean distance of 4.0 mm from the optic disc and 3.0 mm from the center of the FAZ. Echographic characteristics documented a dome-shaped configuration in 77% of eyes, collar button in 16%, and lobulated in 5%, while internal reflectivity was low to low-medium in 79% of tumors (Table 7). Eligible patients who enrolled within the COMS Medium Tumor Trial were slightly older and had larger tumors than those patients who did not enroll [14]. These data suggest excellent internal reliability with no concerns for bias and suggest that enrolled patients were likely at higher risk for all-cause mortality than the cohort of patients who elected not to participate. This supports reasonable cause for external validity and allows the treating clinician to reasonably extrapolate these data to other patients with medium choroidal melanoma meeting the criteria for study eligibility.

The COMS evaluated 6078 patients with choroidal melanoma during the Large Choroidal Melanoma study accrual window [16–18]. A total of 1860 patients had tumors of eligible size; of these, 1302 were eligible for the clinical trial and 1003 enrolled in the randomized study (30% of all tumor patients and 77% of all-size eligible patients) (Table 8). The two principal reasons for the ineligibility of patients with large tumors were other independent primary cancers and greater than 50% of the tumor located within the ciliary body. Eligible patients had a mean age of 60 years, 56% were male, and 97% were non-Hispanic whites. Tumor characteristics at baseline included a mean apical tumor height of 9.5 mm and a longest mean basal diameter of 17.2 mm (Table 9). Echography noted collar-button configuration in 43%, dome shape in 38%, and lobulated in 15%; internal reflectivity was low to lowmedium in 74% of tumors (Table 10). Only 26% of enrolling patients had a visual acuity of 20/40 or better at the time of enrollment (Table 11). Eligible patients who enrolled within the COMS Large Choroidal Melanoma Trial were similar to noneligible patients and to eligible patients who elected not to enroll in the trial with the exceptions that those who enrolled had larger tumor basal diameters, better visual acuity in the fellow eye, and less often had education beyond the high school level. These data, again, confirm high internal validity for the randomized treatment assignments and high external validity, allowing for application of these findings to patients with large choroidal melanoma meeting COMS criteria for study eligibility.

Quality-of-life analysis was included within the COMS study infrastructure to evaluate longitudinal and cross-sectional outcomes for patients treated within the Medium Choroidal Tumor trial [22,23]. In the absence of a survival outcome difference between treatments, along with the known decrease in visual function associated with iodine-125 brachytherapy, patient perceptions of quality of life become increasingly more pivotal to selection of treatment for the individual patient. Quality-of-life data are pending from the COMS and remain the major outcome variable yet to be reported.

The COMS utilized a classic study infrastructure incorporating a multicentered, randomized, prospective evaluation of treatment for medium and large