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The COMS Randomized Trial of Iodine 125 Brachytherapy for Choroidal Melanoma, II: Characteristics of Patients Enrolled and Not Enrolled
COMS Report No. 17
The Collaborative Ocular Melanoma Study Group
Arch Ophthalmol. 2001;119:951-965.
ABSTRACT
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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.
INTRODUCTION
ALTHOUGH RARE, choroidal melanoma is the most common primary intraocular
cancer in adults.1 Enucleation has been the
accepted treatment for primary choroidal melanoma for more than a century
and remains so for large tumors. During the decades that preceded initiation
of the present study, other methods of treatment were proposed as alternatives
to enucleation of eyes containing smaller choroidal melanoma, with the goal
of retaining the eye and possibly useful vision.2-15
Apart from the desire of many patients to retain their eyes, other factors
that stimulated a search for alternatives to enucleation included diagnostic
uncertainty, particularly in the case of smaller tumors, as fine-needle aspiration
of choroidal melanoma typically is not performed, and findings reported by
Zimmerman et al,16-17 which the
authors interpreted to implicate enucleation as a cause of distant metastasis.
These issues are discussed more fully in a separate report.18
At the time the Collaborative Ocular Melanoma Study (COMS) was designed,
radiotherapy was the most promising eye-conserving treatment, whether delivered
by means of charged particles19-22
or an episcleral plaque to which radioactive material was affixed.23-25 Thus, the COMS was
designed to evaluate radiotherapy vs enucleation in the subset of patients
with choroidal melanoma for whom radiotherapy would be considered by ophthalmologists
and patients if it would not reduce survival or increase complications. The
COMS Group elected to conduct 2 randomized trials of radiotherapy for choroidal
melanoma. In each trial, the control arm consisted of patients undergoing
standard enucleation alone. The primary outcome of each trial was death from
any cause; death attributable to melanoma metastasis was the principal secondary
outcome. In the randomized trial for large choroidal melanoma, the radiotherapy
arm consisted of patients undergoing preenucleation external beam irradiation.
Initial findings from that trial have been published.26-28
In the COMS clinical trial that is the focus of this report, iodine 125 brachytherapy
was used. The rationale for selecting 125I as the isotope and a
radioactive plaque delivery system has been presented elsewhere.29-30
A major goal was to evaluate a method of delivering radiotherapy that could
be standardized and made available at many institutions, both within the COMS
organization during the course of the clinical trial and throughout the medical
community if it provided survival rates comparable or superior to those for
enucleation. In addition, this method of radiotherapy delivery was expected
to be applicable to most patients with choroidal melanoma for whom an alternative
to enucleation would be considered by their ophthalmologists.
Accrual of patients to the COMS clinical trial of 125I brachytherapy
was completed on July 31, 1998. The purpose of this report is to describe
the characteristics of the study population and to compare them with characteristics
of patients with tumors of eligible size who were not enrolled. This comparison
permits assessment of the external validity of the trial, that is, the extent
to which patients who participated represent the target population who have
choroidal melanoma and for whom treatment with 125I brachytherapy
could be considered, and, thus, the ability to generalize the findings to
future patients. Survival outcomes as of September 30, 2000, are reported
in a separate article.18
PATIENTS AND METHODS
Descriptions of many aspects of the COMS design and methods have been
published.26, 28-36
The COMS Manual of Procedures37
and the COMS Forms Book38
are available.
INITIAL EVALUATION AND CASE REPORTING
The Data and Safety Monitoring Committee appointed by the director of
the National Eye Institute, Bethesda, Md, approved the study design and methods
on August 27, 1986, prior to initiation of patient evaluation and enrollment.
In addition, the institutional review board of each participating institution
reviewed and approved the COMS protocol and the consent forms used at the
respective clinical center prior to initiation of data reporting and patient
enrollment at individual centers.
Patients with suspected choroidal melanoma were evaluated at 1 of 43
COMS clinical centers for confirmation of the diagnosis and evaluation of
eligibility for one of the COMS randomized trials. All patients for whom the
diagnosis of choroidal melanoma was confirmed clinically by a COMS ophthalmologist
during the enrollment period were reported to the COMS Coordinating Center
(Baltimore, Md) but were identified only by study numbers and code names assigned
at the local clinical centers.
A brief medical and ocular history was elicited before the patient underwent
a detailed ophthalmic examination by a COMS ophthalmologist. The history and
examination addressed the eligibility of the patient and provided baseline
descriptive data. Best-corrected visual acuity was measured on a Bailey-Lovie
chart according to a standard protocol.37 As
part of the ophthalmic examination, the ophthalmologist estimated the tumor
size and provided a detailed description of the tumor location based on distances
from landmark intraocular structures. In particular, the ophthalmologist noted
the location relative to the optic disc when assessing eligibility for enrollment
in the COMS clinical trial of 125I brachytherapy. Estimates of
apical height and longest basal diameter of the choroidal melanoma took account
of both the clinical observations and local measurements from A-scan echograms.
Some patients who were discovered to be ineligible early in the evaluation
process or who refused to consider enrollment in the COMS had examinations
or procedures that deviated from the COMS protocol. Information from the screening
examination was sometimes incomplete for these patients.
Each patient judged to be eligible for the COMS on the basis of the
ophthalmologic examination and medical history was referred to the COMS radiation
oncologist for discussion of radiation issues. The radiation oncologist, a
medical oncologist, or an internist elicited a detailed medical history, performed
a cancer-oriented physical examination, and ordered and interpreted laboratory
studies and an anterior-posterior x-ray film of the chest. A computed tomographic
scan, magnetic resonance images, or biopsy of the liver or other organs was
required by the COMS protocol whenever necessary to rule out metastatic melanoma
or other neoplasms following defined abnormalities in tests of liver function.
For all patients who enrolled in the clinical trial and some early eligible
patients who did not enroll, the Echography Center (currently located in Mars
Hill, NC) reviewed standardized A-scan and contact B-scan echograms for consistency
with the diagnosis and evidence of extrascleral extension, measured the apical
height of the tumor, and classified tumor configuration and internal reflectivity
according to specified criteria.36 Wide-angle
photographs and a fluorescein angiogram with frames taken of all tumor margins
whenever possible were reviewed at the COMS Photograph Reading Center (Iowa
City, Iowa) for consistency with the diagnosis of choroidal melanoma. The
clinical center ophthalmologist was notified whenever extrascleral extension
was noted at the Echography Center and whenever the diagnosis was questioned
by personnel at either of these 2 resource centers.
ELIGIBILITY FOR RANDOMIZED TRIAL OF 125I BRACHYTHERAPY
From November 1986 until July 31, 1998, patients with choroidal melanoma
were evaluated for eligibility for the COMS trial of 125I brachytherapy.
To be considered for this randomized trial, the patient had to have choroidal
melanoma from 2.5 to 10.0 mm in apical height and no more than 16.0 mm in
longest basal diameter. (Until November 1990, the lower and upper limits on
apical height were 3.1 and 8.0 mm, respectively.) Peripapillary tumors (those
with the proximal tumor border 2.0 mm or closer to the optic disc) were eligible
only when the tumor was contained within a 90° angle, with the apex at
the center of the optic disc, and when the enrolling ophthalmologist was confident
that a radioactive episcleral plaque could be placed to cover the entire base
of the tumor and a 2-mm margin beyond the tumor borders apart from the border
proximal to the optic disc. Patients whose tumors were contiguous with the
optic disc were ineligible.
Eligible patients had a primary choroidal melanoma in 1 eye only; were
aged 21 years or older; had no other primary tumor and no history of cancer
other than noninvasive nonmelanotic skin cancer or carcinoma in situ of the
uterine cervix; had no coexisting disease that threatened survival for 5 years
or longer; were judged by the examining oncologist or internist to be free
of metastatic melanoma; had best-corrected visual acuity in the fellow eye
of 20/200 or better; and were able to give informed consent, willing to adhere
to local radiation safety guidelines, and had no condition that would prevent
them from returning for posttreatment follow-up examinations. Previous treatment
for choroidal or ciliary body melanoma in either eye, treatment for any condition
secondary to the tumor, or fine-needle aspiration biopsy of the melanoma rendered
a patient ineligible for the clinical trial. Patients who had extrascleral
tumor extension of 2.0 mm or greater thickness detected during echography
or clinical examination, diffuse, ring, or multifocal tumors, or tumors that
were judged to be located primarily in the ciliary body also were ineligible.
Additional criteria for eligibility are described elsewhere.18, 37
INITIAL TREATMENT
Patients who were judged eligible after completion of all baseline evaluations
were invited to participate in the trial. Those who gave signed consent were
enrolled by means of a telephone call from the local clinic coordinator and
ophthalmologist to the Coordinating Center. During the call, eligibility was
reviewed, and the random assignment to 125I brachytherapy or enucleation
was communicated to the clinical center personnel by Coordinating Center personnel.
Eligible patients who did not enroll selected the management approach
in consultation with their ophthalmologists. The treatment selected was reported
to the Coordinating Center for most eligible patients not enrolled. Reporting
of treatment selected by patients not enrolled because they were judged ineligible
was initiated in September 1989.
DATA COLLECTION, MANAGEMENT, AND ANALYSIS
Data from clinical evaluations and from review of echograms were recorded
on standard forms38 and forwarded to the Coordinating
Center for transcription to computer files, automated and manual edits for
consistency and protocol adherence, and data analysis. At several points in
the course of the COMS, the investigators evaluated individual data collection
items with respect to their contributions to the primary and secondary outcomes
of the trials and to improved knowledge of choroidal melanoma. Some changes
were made at the time of each of these reviews. Therefore, some information
was collected during only part of the enrollment period and is available for
only a subset of enrolled patients. Less information was requested for patients
who did not enroll than was required for those who enrolled. Data missing
for these 2 reasons are categorized as "not available" in the tables. Eligibility
of patients who enrolled in the trial and reasons for ineligibility and for
nonparticipation of eligible patients were confirmed during review of clinic
records and chart notes as part of routine visits by COMS clinic monitors
to participating clinical centers.
Only 1 record was retained in the database for each patient reported
to the COMS. Comparisons were performed twice yearly to assure that each patient
reported by more than 1 center was counted only once.26
The most recent eligibility and enrollment status of each patient reported
was retained for all data analyses.
Data reported herein are from baseline examinations, central reviews
of baseline materials, and any corrections to baseline data that were received
at the Coordinating Center by September 30, 2000. Data displays are primarily
descriptive in nature. Statistical tests were used to determine whether there
were informative differences between patients who were and were not eligible
for the trial with respect to characteristics of patients and choroidal melanoma
reported for both groups and to compare eligible patients who enrolled in
the trial with those who did not. The Wilcoxon rank sum test was used to compare
distributions of continuous variables.39 The  2 test for trend in ordered categories40
was used to compare distributions of categorical variables in 3 or more qualitatively
or quantitatively ordered categories. The 2 test for homogeneity39 was used to compare dichotomous distributions and
distributions in which the categories have no inherent qualitative or quantitative
order.
RESULTS
REASONS FOR INELIGIBILITY AND NOT ENROLLING
As of July 31, 1998, 8712 patients with choroidal melanoma of all sizes
had been evaluated at COMS clinical centers and reported to the Coordinating
Center; 5046 patients (58%) had tumors that met the size requirements for
this clinical trial. Of 2164 patients with tumors of appropriate size who
were ineligible for the trial(43%), 470 (22%) failed to meet 2 or more of
the eligibility criteria. The most common reasons for exclusion of the remaining
1694 patients were proximity (183 patients) or contiguity (495 patients) of
the tumor to the optic disc, which precluded protocol treatment with an episcleral
radioactive plaque (40%); 1 or more other primary cancers (332 patients, 20%);
and melanoma that was predominantly in the ciliary body (193 patients, 11%).
These reasons were also those most often reported for patients ineligible
for 2 or more reasons; the corresponding numbers and percentages for these
470 patients were 179 (38%), 166 (35%), and 136 (29%). The contralateral eye
of 5 patients otherwise eligible for this clinical trial had an earlier or
simultaneous diagnosis of choroidal melanoma; 5 more patients with bilateral
choroidal melanoma were ineligible for additional reasons. Twenty-one patients
were diagnosed as having metastatic melanoma at time of evaluation for the
COMS. Twenty-four patients were ineligible because they were younger than
21 years; young age was the only reason for ineligibility for 15 of these
24 patients.
Of 2882 patients judged eligible for enrollment, 1317 (46% of eligible
patients; 26% of all patients with choroidal melanoma of appropriate size)
gave signed consent, enrolled, and were assigned randomly to enucleation or
to an 125I radioactive plaque. Management preferences of the patient
or of the referring or COMS ophthalmologist accounted for the decision of
1143 (73%) of the 1565 eligible patients not enrolled. Unwillingness of the
patient to accept random assignment of treatment accounted for 345 more (22%).
INITIAL TREATMENT ELECTED BY PATIENTS NOT ENROLLED
Of the 1537 eligible patients not enrolled for whom initial treatment
of the tumor was reported, 469 (31%) selected enucleation, either alone or
following preenucleation radiation; 887 (58%) selected radioactive plaque,
either alone or in combination with laser photocoagulation to the tumor borders;
27 (2%) had other types of eye-conserving radiotherapy; 27 (2%) had other
types of treatment, and 127 (8%) initially were observed without treatment.
Of the latter group, 71 (56%) had choroidal melanoma with apical heights in
the range 2.5 mm to 3.0 mm.
The treatment selected was reported for 1741 ineligible patients. Among
these patients, 674 (39%) had the eye enucleated, 720 (41%) had some type
of eye-conserving radiotherapy, and 210 (12%) were observed without treatment
initially. Of the latter group, 59 had another primary cancer, 23 had undergone
treatment of the tumor prior to evaluation for the COMS, 19 had another life-threatening
condition, and 6 had melanoma metastases.
BASELINE DEMOGRAPHIC CHARACTERISTICS
Demographic characteristics of the patients enrolled in the randomized
trial are displayed in Table 1.
Characteristics of eligible patients not enrolled and of patients who had
choroidal melanoma that met the size criteria but who were not eligible for
enrollment are given for comparison. A detailed analysis of sociodemographic
and clinical factors potentially predictive of enrollment in the COMS trials
is reported elsewhere.41
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Table 1. Demographic Characteristics of Eligible and Ineligible Patients
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Ineligible patients were older than eligible patients (Table 1; P<.001), with mean ages of
64 years and 59 years, respectively. Eligible patients who enrolled were somewhat
older than eligible patients who did not enroll (P
= .04). Nearly identical numbers of men and women were in each eligibility
and enrollment category (Table 1).
Almost all patients with choroidal melanoma were non-Hispanic white, regardless
of whether eligible for the COMS clinical trial; this finding is consistent
with the epidemiology of this cancer.42 Two
American Indians evaluated for the COMS had tumors of eligible size; one was
eligible and enrolled but the other was ineligible. These 2 cases were reported
earlier by the COMS Group.43
TUMOR CHARACTERISTICS
Of the patients who enrolled in the clinical trial, 944 (72%) were evaluated
at a COMS center within 30 days of the initial diagnosis of choroidal melanoma
(Table 2). For enrolled patients,
the median interval from diagnosis to evaluation for the COMS was 9 days and
from diagnosis to enrollment was 20 days. Median time from diagnosis to evaluation
at a COMS clinical center was 8 days for patients who were eligible but did
not enroll and 7 days for those who were ineligible.
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Table 2. Characteristics of Choroidal Melanoma in Eligible and Ineligible
Patients*
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Choroidal melanoma was diagnosed with similar frequency in right and
left eyes in all groups of patients (Table
2). The mean apical height of the tumor was similar for eligible
patients who enrolled (4.8 mm) and who did not enroll (4.7 mm); however, the
distributions of apical height differed (P = .001)
with patients who enrolled having tumors of greater apical height. The distributions
of apical height also differed between eligible and ineligible patients (P<.001), with ineligible patients having thicker tumors
(Table 2). Although the mean longest
basal tumor diameter was similar in eligible patients who enrolled (11.4 mm)
and those who did not (11.1 mm), these distributions also differed (P = .005), with more enrolled patients having tumors with
longer basal diameters. Both the means and the distributions of longest basal
tumor diameter were similar for all eligible patients combined and ineligible
patients.
Findings from the ophthalmologist's description of tumor location relative
to intraocular landmarks are summarized in Table 3. The locations of the most anterior and posterior borders
of the choroidal melanoma were reported for all but 32 eligible patients.
For 97% of eligible patients, regardless of the enrollment decision, the posterior
border was posterior to the equator; for the remaining eligible patients,
the most posterior portion of the tumor border was between the equator and
the ora serrata. In contrast, of the 1291 ineligible patients for whom the
information was reported, the posterior tumor border was anterior to the equator
in 183 (14%). Differences also were noted between eligible and ineligible
patients and between eligible patients who enrolled and those who did not
enroll with respect to the location of the most anterior border of the tumor
(P<.001 and P = .01,
respectively). Among eligible patients who enrolled, 45% had the most anterior
border of the choroidal melanoma anterior to the equator compared with 50%
of eligible patients who did not enroll. The anterior tumor border was anterior
to the equator in 44% of the 1284 ineligible patients for whom the information
was reported; in 4% the tumor extended into the anterior chamber angle, and
in 5% the tumor invaded the iris.
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Table 3. Ophthalmologic Assessment of Location of Choroidal Melanoma
in Eligible and Ineligible Patients*
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More ineligible patients than eligible patients had the tumor apex over
the fovea (Table 3). Nearly half
(48%) of the patients who enrolled had choroidal melanoma with the apex temporal
to the fovea compared with eligible patients who did not enroll (40%) and
ineligible patients (29%). However, in all 3 groups of patients, more patients
had tumors with the apex in the quadrant temporal to the fovea than in any
of the other 3 quadrants. Among eligible patients, the tumor apex was located
least often in the quadrant nasal to the fovea, owing in part to the eligibility
criteria regarding tumor proximity to the optic disc.
Distance between the proximal borders of the choroidal melanoma and
the optic disc and distance from the center of the foveal avascular zone to
the proximal border of the tumor were reported primarily for patients who
enrolled. The information was collected only through 1989 for eligible patients
who did not enroll and is available for only 159 (10%) of these patients (Table 3). However, among this early group
of eligible patients who did not enroll, the distance between the tumor and
the optic disc borders tended to be longer than for patients who enrolled
(P = .06). Similarly, the distance between the tumor
and the center of the foveal avascular zone tended to be greater among the
same group (P = .005). Among patients who enrolled,
some part of the tumor overlay the center of the foveal avascular zone in
190 (15%).
Tumor shape or configuration was classified centrally from echograms
for all patients who enrolled and for 467 patients reported during the first
3 years of patient accrual who were eligible but did not enroll (Table 4). The most common shape or configuration
of the choroidal melanoma among eligible patients was dome, accounting for
77% of both patients who enrolled and those who did not. Collar button configurations
were noted in only 207 (16%) of enrolled patients and 55 (13%) of the initial
group of eligible patients not enrolled. Internal reflectivity of the tumor
was added to the central assessment after patient accrual was underway; it
was evaluated from baseline echograms for all patients who enrolled but for
only 83 eligible patients not enrolled. Almost all of the tumors among these
eligible patients were judged to have low to medium internal reflectivity;
only 112 enrolled patients (9%) had internal reflectivity classified as medium-high,
high, very high, or irregular. Other characteristics of the choroidal melanoma
among patients who enrolled are described elsewhere.18
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Table 4. Echographic Characteristics of Choroidal Melanoma in Eligible
Patients Enrolled and Not Enrolled*
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VISUAL ACUITY
As given in Table 5, eligible
patients who enrolled had worse visual acuity in the eye with choroidal melanoma
but better visual acuity in the fellow eye than eligible patients who did
not enroll (P<.001). Ineligible patients had worse
visual acuity in both eyes than eligible patients (P<.001).
More than one third (35%) of eligible patients had a visual acuity of 20/20
or better in the affected eye at the time of evaluation for this trial compared
with 17% of ineligible patients. More than twice as many ineligible patients
as eligible patients, 18% vs 7%, had visual acuity worse than 20/200 in the
eye with choroidal melanoma.
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Table 5. Baseline Visual Acuity of Eligible and Ineligible Patients*
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Approximately two thirds of eligible patients but fewer than half of
the ineligible patients had a visual acuity of 20/20 or better in the fellow
eye (Table 5). Older age of ineligible
patients only partially accounted for worse visual acuity in the fellow eye.
In each age stratum, the visual acuity of fellow eyes of ineligible patients
was worse than that of fellow eyes of eligible patients (data not shown).
COMMENT
Apart from slightly older ages among patients who enrolled in the COMS
clinical trial of 125I brachytherapy, eligible patients who enrolled
and eligible patients who did not enroll had similar demographic characteristics.
Choroidal melanoma of patients who enrolled were somewhat greater in apical
height than those of eligible patients who did not enroll. The most frequent
reason for deeming patients ineligible for enrollment was tumor proximity
to the optic disc, which rendered the patient an unsuitable candidate for
a radioactive plaque by COMS criteria. Thus, patients who enrolled in the
clinical trial represent a subset of the target population of patients who
have choroidal melanoma of the specified size.
EFFECT OF ELIGIBILITY AND EXCLUSION CRITERIA
Periodic evaluation of reasons patients were judged ineligible for enrollment
led to reevaluation of exclusion criteria and some refinements and changes
in eligibility criteria during the patient accrual period. Selection of an
episcleral plaque with 125I seeds as the radiotherapy method to
be evaluated resulted in adoption of eligibility criteria specific to this
delivery system, namely restrictions regarding the proximity of choroidal
melanoma to the optic disc to permit the surgeon to position the plaque over
the tumor base and to provide an acceptable margin for positioning errors.29 When it became apparent after several years of patient
accrual that the primary reasons for ineligibility related to proximity of
the choroidal melanoma to the optic disc in otherwise eligible patients, consideration
was given to several approaches to evaluating radiotherapy in comparison to
enucleation for these cases. One possibility considered was to include such
cases in the clinical trial in a separate stratum, with random assignment
to 125I brachytherapy or enucleation using a plaque designed specifically
for peripapillary and juxtapapillary tumors. Concerns regarding this approach
included the difficulty of plaque placement next to the optic nerve; the possibility
that radiation dosimetry calculations would be incorrect owing to placement
errors, and, therefore, the possibility that the tumor apex would not receive
the prescribed dose of radiation; and increased risk of undetected tumor extension
along the optic nerve that would not be irradiated. Thus, pooling of data
across all patients assigned to 125I brachytherapy would be problematic.
Another possibility considered was to design a separate trial for patients
who had choroidal melanoma located close to the optic disc but to use a different
radiotherapy delivery system (eg, teletherapy). This approach was rejected
because it was judged to be unlikely that a sufficient number of patients
in this category would be available to enroll by the projected end of accrual
to other COMS clinical trials. The third approach, and the one adopted, was
to make no modification to the COMS protocol and to accept the fact that a
sizable number of patients in the target population had been excluded from
the clinical trial and that the findings from the trial could not be extrapolated
reliably to such patients.
This experience has emphasized one of the difficulties encountered when
designing a clinical trial for a rare condition. Before the COMS was initiated,
there were no estimates from large case series of the proportion of choroidal
melanoma patients in whom the proximal tumor border abutted the optic disc
or extended closer than 2 mm to it. Thus, the proportion of patients who would
be screened for the COMS and whose tumor location would be unsuitable for
a radioactive plaque was unknown. The COMS has documented that a substantial
fraction of all patients who have choroidal melanoma of a size judged suitable
for brachytherapy have tumors that extend 2 mm or closer to the optic disc:
16% of eligible patients who enrolled, 17% of eligible patients who did not
enroll for whom the information was reported, and 40% of patients ineligible
for a single reason. Thus, more than 1000 patients in this category were evaluated
for this COMS clinical trial, of whom only 216 were judged by their ophthalmologists
to meet the strict eligibility criteria and enrolled.
The second most frequent reason for ineligibility of patients for the
randomized trial was current or past diagnosis of another primary cancer apart
from carcinoma in situ of the uterine cervix or nonmelanotic, noninvasive
skin cancer. The contribution of this exclusion criterion was recognized early
in the accrual period.44 However, little consideration
was given to modifying this criterion because of the potentially confounding
effect on comparison of treatment arms for overall and melanoma-related mortality
and because of the effects of other treatments these patients may have received.
REPRESENTATIVENESS OF COMS PATIENTS
Although patients who enrolled in this clinical trial were a selected
subgroup of all patients with choroidal melanoma evaluated at COMS clinical
centers, a key question is whether they were representative of patients who
would be candidates for treatment with 125I brachytherapy. Eligible
patients who enrolled have been compared with eligible patients screened at
COMS centers but who did not enroll to the extent permitted by COMS data collection
policies and practices. These 2 groups of patients were found to be similar
with respect to many characteristics believed to be predictive of survival
outcomes but to differ with respect to tumor size. Table 6 gives the characteristics of the choroidal tumors and of
patients enrolled in this COMS clinical trial compared with those in other
published studies of 125I brachytherapy.45-55
For each characteristic displayed, there was considerable variability among
studies, with metrics of characteristics of COMS patients consistently contained
within the distributions represented by other studies. Thus, patients who
enrolled in the COMS randomized trial of 125I brachytherapy vs
enucleation are similar to those reported by others who underwent 125I brachytherapy using an episcleral plaque. These comparisons provide
additional support of the external validity of the COMS trial.
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Table 6. Baseline Characteristics of Patients Included in Reports of
Treatment of Choroidal Melanoma With Iodine 125 Brachytherapy*
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As reported, ineligible patients were older than eligible patients (Table 1). Older age among ineligible patients
has been reported for other cancer trials. Hunter et al56
reported that age criteria for eligibility and greater prevalence of comorbid
conditions among older individuals resulted in decreased eligibility among
cancer patients for whom a protocol was available in the Community Clinical
Oncology Program. In a recent report by Hutchins et al57
based on experience of the Southwest Oncology Group, older patients were found
to be more likely to be ineligible. These investigators cited stringent eligibility
criteria, coexisting medical conditions, and logistic barriers to participation
of elderly patients. In the COMS, there was no upper age limit for eligibility.
However, the prevalence of coexisting disease and other primary cancers was
higher in older patients than younger ones. The enrolling physician considered
patients' medical history and any concurrent health problems, apart from choroidal
melanoma, when assessing the prognosis for 5-year survival after enrollment.
Although age was to be ignored when making this assessment, some investigators
reported difficulty ignoring the age of patients in their 80s and 90s, even
when they were in good health. Nevertheless, only 56 patients (3%) were judged
ineligible solely because they were not expected to live for at least 5 years.
VALUE OF COMPLETE CASE REPORTING
A complete accounting for all patients screened for a clinical trial
has been advocated by some clinical trialists, including the authors of the
CONSORT statement.58 Such an undertaking often
poses daunting logistical difficulties because it is not always simple to
identify those individuals who have been screened. For example, a patient
referred for screening because the target diagnosis or condition is suspected
may have a different diagnosis or condition. Thus, criteria for those to be
counted as screened must be established if the final accounting is to be meaningful.
Few clinical trials in ophthalmology have attempted to report the total number
of patients screened for the trial. Among clinical trials in cardiology, the
Coronary Artery Surgery Study59 defined the
group of patients screened for the trial, described those who enrolled ("randomized"),
compared them with those who were eligible but did not enroll ("randomizable"),
and published survival outcomes for randomized and randomizable patients.59-60
Because choroidal melanoma is a rare condition, it was simple to define
the patients to be reported in the COMS. As discussed earlier,26, 31, 41
a decision was made during the COMS planning phase to collect demographic
and clinical information for all patients referred to a participating clinical
center for whom a diagnosis of choroidal melanoma was confirmed by a COMS
ophthalmologist during the period of patient accrual. The primary purpose
of collecting such information was to project the dates by which the target
numbers of patients would be enrolled in the individual clinical trials and
to estimate screening workloads at the clinical centers. However, collection
of such information permitted assessment of the representativeness of the
patients enrolled in COMS randomized trials and should provide substantial
increases in knowledge of the epidemiologic and clinical characteristics of
this primary ocular cancer.
Within the COMS multicenter organization, descriptive information has
been assembled centrally for 8712 patients with choroidal melanoma who were
evaluated during the 11.5-year period of patient accrual. During that time,
COMS ophthalmologists examined an average of more than 700 patients with choroidal
melanoma each year. Based on an estimated incidence rate of 6 to 8 cases per
million population per year, these 8712 patients are believed to have comprised
35% to 40% of all of the incident cases of choroidal melanoma diagnosed in
the United States and Canada during that time period. This large fraction
of the choroidal melanoma patient population further supports the external
validity of findings from the randomized trial. Based on known incidence rates
of common eye conditions such as diabetic retinopathy and neovascular age-related
macular degeneration, the proportion of all available patients who participated
in the COMS is much greater than the proportion who have participated in completed
clinical trials of treatments for those conditions.
In earlier reports, characteristics have been summarized for 1860 patients
with large choroidal melanoma evaluated for the COMS randomized trial of preenucleation
radiation vs enucleation alone26 and for 300
patients with small choroidal melanoma evaluated for a nonrandomized prospective
study.61 In the present report, characteristics
of 5046 patients with choroidal melanoma of an intermediate size judged suitable
for randomization to 125I brachytherapy or enucleation have been
summarized. From December 1994, when accrual to the COMS clinical trial for
large choroidal melanoma was completed, through July 1998, when accrual to
the clinical trial of 125I brachytherapy vs enucleation was completed,
635 additional patients with large choroidal melanoma were evaluated at COMS
clinical centers and reported. Through July 1998, 1171 patients with small
choroidal melanoma were reported to the COMS Coordinating Center. Information
from all 8712 patients will be pooled and presented in future reports from
the COMS Group.
GENERALIZABILITY OF FINDINGS FROM THE RANDOMIZED TRIAL
Can findings from the COMS randomized trial be extrapolated to patients
who would not have met the eligibility criteria? The primary reason for ineligibility
was that the tumor was located too close to the optic nerve for reliable placement
of the radioactive plaque and for optimal delivery of radiation to the tumor.
Mortality rates, complication rates, or both may be higher in these patients.
The second most common reason for exclusion was a current or past diagnosis
of another primary cancer. With progress in developing treatments that have
prolonged survival and achieved apparent cure for some cancers, it may be
appropriate to extrapolate findings from this trial to some patients diagnosed
with choroidal melanoma with an earlier diagnosis of another cancer with no
evidence of recurrence who meet all other COMS eligibility criteria. However,
the COMS randomized trial will provide little or no data to support or refute
the validity of this conclusion. Resources have not permitted follow-up for
mortality or other outcomes among patients who did not enroll in the randomized
trials. When considering treatment options, the ophthalmologist and the patient
with choroidal melanoma must consider how well COMS findings are likely to
apply to the individual patient based on how closely the patient meets COMS
criteria for enrollment.
Through randomization to minimize bias and confounding and through attention
to quality assurance and monitoring in the COMS, the randomized trials have
high internal validity. External validity depends on the degree to which enrolled
patients represent the population of patients with choroidal melanoma who
would be candidates for both treatments evaluated. In the COMS, there were
few differences in demographic or tumor characteristics between eligible patients
who enrolled and those who did not that would be considered clinically and
statistically significant. Furthermore, published data suggest that COMS patients
who enrolled were similar to other patients with choroidal melanoma who were
treated with 125I brachytherapy by other physicians, further evidence
to support the external validity of the trial. Therefore, findings from this
COMS trial, some of which are reported in this same issue of the ARCHIVES,
can be applied with confidence to patients who meet the criteria used to establish
eligibility for this COMS trial.
THE COMS GROUP AS OF SEPTEMBER 30, 2000
PARTICIPATING CLINICAL CENTERS AND PERSONNEL
Kellogg Eye Center, Ann Arbor, Mich: Principal
Investigator: Andrew K. Vine, MD; Clinic Coordinator: Julie M. Willis, LPN,
COMA; Ophthalmologists: Bartley Frueh, MD; Kamel Itani, MD, 1989-1990; Ron
M. Kurtz, MD, 1996-2000; Scott R. Sneed, MD, 1989-1992; Radiation Oncologists:
James A. Hayman, MD; Cornelius J. McGinn, MD; Richard Diaz, MD, 1986-1987;
Allen S. Lichter, MD, 1987-1999; John M. Robertson, MD, 1992-1995; Sonja Schoeppel,
MD, 1988-1991; Radiation Physicists: Randall Ten Haken, PhD; Antoinette V.
Thompson, MS, 1995-1997; Echographer: Kathleen A. Meyer, RDMS; Photographers:
Sally Ann Stanley; Csaba Martonyi, 1986-2000; Ophthalmic Pathologists: Victor
Elner, MD, PhD; Marilyn Kincaid, MD, 1986-1987; Reimer J. Wolter, MD, 1988-1993. Emory Eye Center, Atlanta, Ga: Principal Investigators:
Paul Sternberg, Jr, MD; Travis A. Meredith, MD, 1986-1990; Clinic Coordinator:
Jayne M. Brown; Ophthalmologists: Thomas M. Aaberg, Jr, MD; Thomas M. Aaberg,
Sr, MD; Ted H. Wojno, MD; Radiation Oncologists: James W. Keller, MD; Jerome
Landry, MD; Ian R. Crocker, MD, 1992-1995; John McLaren, MD, 1986-1993; Radiation
Physicists: Christopher A. Aguilera, MS, 1991-1997; Elizabeth Butker, MS;
Kathleen A. Klee, PhD; David Strongosky, MMSc, 1987-1988; Visual Acuity Examiners:
Deborah K. Gibbs, COT; Linda T. Curtis, COA, 1986-1993; Ann Fremstad, COT,
1991-1994; Echographers: Rhonda G. Waldron, COMT; Alice Ward, 1986-1990; Photographers:
James Gilman, CRA; Robert A. Myles; Chris Snipes, 1987; Ray Swords, CRA, 1987-1999;
Ophthalmic Pathologists: Hans E. Grossniklaus, MD; F. Phinizy Calhoun, Jr,
MD, 1988-1993; Wallace Campbell, MD, 1987-1989. Piedmont
Hospital, Atlanta: Principal Investigators: James H. Frank, MD; William
H. Jarrett, II, MD, 1986-1998; Ophthalmologists: Robert L. Halpern, MD; William
S. Hagler, MD, 1986-1998; Radiation Oncologists: Norman Jones, MD; Fred P.
Schwaibold, DO; Mark Jones, MD, 1993-1994; Radiation Physicists: Peter Mondalek,
1987-1989; Karol J. Wynn, CMD; Visual Acuity Examiners: Gail A. Degenhardt,
COA; Angela R. Muncey, COA; Jon Aaron, COT, 1986-1994; David S. Bolerjack,
COA, 1990-1991; Christine E. Cooper, 1998-1999; Erin K. Hulsey, COA, 1996-1998;
Lisa Kailey, COA, 1996-1997; Debbie H. Lee, COA, 1990-1998; Susan N. McCart,
1991-1995; Gail A. McCoy, 1991-1995; Photographers: Mark E. Clark; Ben Baxter,
1987-1989; Bambi P. Robinson, CRA, 1991-1993; Kenneth D. Thompson, 1986-1999;
Kelly K. Wilson, 1992-1996. The Wilmer Ophthalmological
Institute, Baltimore, Md: Principal Investigator: Andrew P. Schachat,
MD; Clinic Coordinators: Warren T. Doll, Jr, COA; Ellen F. Greenberg, COT;
Mike Hartnett, COT; Marguerite Alexander, RN, BSN, 1986-1995; Susan Kaiser,
1988-1989; Catherine S. Sackett, RN, CANP, 1989-1993; Ophthalmologist: Nicholas
T. Iliff, MD; Radiation Oncologist: Ding J. Lee, MD, PhD; Radiation Physicists:
Juan F. Jackson, 1990-1998; Joseph Ianitto, 1987-1990; Wing-Chee Lam, PhD,
1987-1992; Visual Acuity Examiner: Linda T. Pollack, CO, 1988-1993; Echographer:
Cathy DiBernardo, RN, RDMS; Photographers: Dennis Cain; David Emmert; Terry
George, 1986-2000. Retina Associates of Cleveland, Beachwood,
Ohio: Principal Investigators: Z. Nicholas Zakov, MD; Thomas A. Rice,
MD, 1987-1997; Clinic Coordinators: Kristen Dempsey; Geraldine Daley, CRA,
1997-2000; Dina Preseren, 1988-1991; Ophthalmologists: Scott D. Pendergast,
MD; Hernando Zegarra, MD; Radiation Oncologist: Donald Shina, MD; Radiation
Physicists: Ned Began, MS, 1987-1998; Kunjan Pillai, MS, 1987-1998; Visual
Acuity Examiners: Kimberly A. DuBois, COA; Mary A. Ilc, COT; Connie S. Keller,
COA; Donna Knight, COT; Stephanie A. Schura, COA; Kathy Coreno, 1989-1994;
Echographers: Pamela Rowe, CRA; Kelly Smith, CRA, COT, 1989-1994; Photographer:
Sheila Smith-Brewer, CRA, COMT. Schepens Retina Associates,
Boston, Mass: Principal Investigator: Clement Trempe, MD; Clinic Coordinator:
Zena F. Nies; Ophthalmologist: John Weiter, MD; Radiation Oncologists: Mison
Chun, MD, 1986-1989; David E. Wazer, MD, 1989-1994; Radiation Physicist: Kenneth
Ulin, PhD, 1988-1994; Visual Acuity Examiners: Gerald Friedman, OD; Rodney
Immerman, OD; Echographers: Alex Jalkh, MD; Fernando Acosta, MD, 1990-1993;
Fadi Nasrallah, MD, 1987-1989; Miguel A. Quiroz, MD, 1989-1990; Photographers:
Dennis C. Donovan; Thomas O'Day, 1987-1995; Andrew Rosenblum, 1986-1989; Cheryl
Weber, 1986-1988. Atlantic Eye and Face Center, Cary, NC: Principal Investigator: Jonathan J. Dutton, MD, PhD; Clinic Coordinators:
Marianne Heston, CMA, COT, 1986-1989; Cynthia Lyons, 1994-1997; Kim K. Peddle,
COT, 1994-2000; Barbara A. Schuh, COT, 1990-1994; Ophthalmologist: Christopher
M. DeBacker, MD, 1998-1999; Radiation Oncologists: Mitchell S. Anscher, MD;
Edward Halperin, MD; Lawrence B. Marks, MD; Kenneth Leopold, MD, 1988-1993;
Gustavo Montana, MD, 1987-1994; Jeffery D. Morton, MD, 1995; Gregory S. Sibley,
MD, 1996-1998; Angel E. Torano, MD, 1992-1993; Radiation Physicists: Gunilla
C. Bentel, RN, RTT; Thaddeus Samulski, PhD; Photographers: Beth Ann Benetz,
CRA, 1989-1994; Nancy E. Knight, CRA, COA, 1991-1994; Ruth Schirmer, CRA,
1987-1997; Ophthalmic Pathologist: Alan Proia, MD, PhD, 1987-1992. University of Virginia, Charlottesville: Principal Investigator: Brian
P. Conway, MD; Clinic Coordinators: Mary Jonni Henofer, RN, CRNO; Diana Robertson,
1989; Ophthalmologists: James S. Tiedeman, MD, PhD; Marianne Cowley, MD, 1989-1993;
Eleanore M. Ebert, MD, MPH, 1993-1996; Radiation Oncologists: William C. Constable,
MD; James M. Larner, MD; Michela Caruso, MD, 1992-1994; Cynthia Spaulding,
MD, 1989-1992; Radiation Physicists: Alan Aqualino, PhD, 1989-1996; Gilbert
D. Glennie, ME Biomed, 1995-1998; Janelle A. Molloy, PhD; Visual Acuity Examiners:
James S. Chisholm, COT; Patsy Overstreet, RN, COT; Lillian L. Shoffstaff-Tyler,
COT; L. Sharon Hoyle, COMT, 1992-1994; Ellen T. Murphy, AS, COA, 1993-1994;
Melanie Smith, COT, 1994-1995; Karen L. Summerville, COMT, 1994-1995; Photographers:
Jane G. Fleming; James Scott. Northwestern University, Chicago,
Ill: Principal Investigators: Lee M. Jampol, MD; James Puklin, MD,
1987-1989; Clinic Coordinators: Jill M. Koecher; Beth Chiappetta, RN, 1993-2000;
Gail Daubert, RN, 1987-1993; Mimi S. Mansfield, 1996-1997; Ophthalmologists:
Mark Daily, MD; Gary S. Lissner, MD; Robert Schroeder, MD; David V. Weinberg,
MD; Richard G. Gieser, MD, 1990-2000; Larry Wood, MD, 1991; Radiation Oncologists:
Bharat B. Mittal, MBBS; William Small, Jr, MD; Ramananda Shetty, MD, 1986-1996;
Radiation Physicist: Patricia Johnson, DSc, 1987-1998; Visual Acuity Examiners:
Zuzanna Strugala, COA, MA; Michael Giese, OD, 1987-1991; Edgar S. Perez, OD,
1992-2000; Jeff M. Scurry, 1993-1995; Renata Swigost, 2000; Barbara A. Tallman,
COT, 1991-1992; Echographers: Robert A. Levine, MD; William Myers, MD, 1986-1993;
Photographers: John M. Gerty, CRA; Alexander Habib; Ned Bezinovich, 1988-1992;
Karen Parque, 1988-1993; Leonard S. Richine, 1988-1998; Gloria J. Valadez,
1995-1996; Ophthalmic Pathologist: Richard O'Grady, MD, 1987-2000; Following
Oncologists: Steven B. Newman, MD; John M. Shaw, MD. University
of Illinois, Chicago: Principal Investigators: Norman P. Blair, MD;
Morton F. Goldberg, MD, 1985-1989; Clinic Coordinators: Dorris Brown-Hutchins,
1988-1998; Moira Keating, 1986-1987; Christine Mullahy, COT, 1993-2000; Ophthalmologists:
Steven B. Cohen, MD, 1986-1989; Kenneth I. Resnick, MD, 1990-1999; Radiation
Oncologist: Edwin Liebner, MD, 1986-1995; Radiation Physicist: Richard Haas,
1987-1995; Visual Acuity Examiners: Andrew Cross, COT; Dorothe Ernest, MA,
ACSW, 1989-1990; Echographers: Carolyn Anderson, MD, 1993-1995; Leonard Kut,
MD, 1987-1992; Photographer: Norbert Jednock. Cleveland
Clinic Foundation, Cleveland, Ohio: Principal Investigator: Froncie
A. Gutman, MD; Clinic Coordinators: Laura Holody, COA; Susan E. Lichterman,
RN; Tina E. Kiss, COT, CCRA, 1994-1997; Vivian Tanner, COT, 1987-1993; Ophthalmologists:
Jill A. Foster, MD; John S. Ambler, MD, 1989-1990; John V. Linberg, MD, 1990-1991;
Radiation Oncologists: Rashad El Dabh, MD, 1988-1990; Robert M. Fine, MD,
1993-1998; Jerrold P. Saxton, MD, 1990-1997; Radiation Physicists: Patrick
Higgins, PhD, 1987-1994; Debbie A. Jenkins, PhD, 1993-1994; Claudio H. Sibata,
PhD, 1989-1990; Visual Acuity Examiner: Susannah Hanson, CO, 1987-1997; Echographers:
Karen A. King, COT; LuAnne Sculley, COMT, RDMS; Louise Berlin, 1987-1989;
Cate A. Reinhard, 1993-1996; Photographers: Deborah Ross, CRA; Roberta Abram,
CRA, 1986-1990; Michael P. Kelly, 1995-1999; Pamela J. Vargo, 1995-1996; Ophthalmic
Pathologist: Careen Lowder, PhD, MD. Ohio State University,
Columbus: Principal Investigator: Frederick H. Davidorf, MD; Clinic
Coordinators: Cynthia S. Taylor; Jean Bildsten, RN, 1986-1990; Susan E. Cornetet,
1991-1993; Ophthalmologist: Robert B. Chambers, DO; Radiation Oncologists:
Constance J. Bauer, MD; Subir Nag, MD; Sheila E. Hodgson, MD, 1987-2000; Radiation
Physicists: Christos Kanellitsas, PhD; Nina Samsami, PhD; Cheng M. Su, PhD,
1989-1991; Visual Acuity Examiners: Chhanda Chaudhuri, COA; Jill D. Milliron,
COA; Jerilyn G. Perry, COT, ABO; Nanci J. Cover, COA, 1992-1995; Gail Shortlidge,
1987-1995; Echographer: Paula Andrzejewska, 1992-1993; Photographers: Michael
J. Keating; Scott J. Savage, EMT-A; R. Michael Clark, CRA, 1986-1990; Debra
Weisenburger, CRA, 1989-1992; Following Oncologist: Gregory J. Lavalle, MD,
1997-1999. Texas Retina Associates, Dallas: Principal
Investigator: Dwain G. Fuller, MD; Clinic Coordinators: Sally A. Arceneaux,
COST, COA; Jean Arnwine; Theresa Anderson, COA, 1986-1997; Ophthalmologists:
Gary Edd Fish, MD; William Snyder, MD; Radiation Oncologist: Donald Schwarz,
MD; Radiation Physicists: William F. Gagnon, PhD; David B. Hammond, ABMP;
Gregory McDaniel, PhD; Visual Acuity Examiners: Diane Conway, 1987-1988; Denise
Dalrymple, 1987-1991; Cynthia Nork, 1987-1995; Echographers: Sandra Sue Solomon;
Beth A. Pieczynski, COA, 1991-1998; Randal Straach, 1987-1995; Photographers:
Hank Aguado; Bob H. Boleman; Richard E. Jones; Richard Evans, CRA, 1988-1989;
John G. King, 1998-2000; Ruth Picchiottino, 1986-1987; Kevin Rose, 1988-1989;
Ophthalmic Pathologist: Martha Luckenbach, MD, 1987-1989. Porter Adventist Hospital/Centura Health, Denver, Colo: Principal Investigator:
Kenneth R. Hovland, MD; Clinic Coordinator: Suzette Compton, RN; Ophthalmologists:
Douglas L. Holmes, MD; David W. Johnson, MD; Stephen T. Petty, MD; John Pope,
Jr, MD; John D. Zilis, MD; Matthew W. Wilson, MD, 1997-1999; Radiation Oncologists:
Seth D. Reiner, MD; David S. Shimm, MD; Wendy M. Nekritz, MD, 1997-1998; David
P. Schreiber, MD, 1989-1997; Amanda J. Story, MD, 1991-1992; Radiation Physicists:
Kari L. Cann, MS; Gary W. Douglas, MSc; Michael J. Bailey, MS, 1990-1996;
Gregory Burns, MS, 1989-1990; J. Donald Russell, MS, 1991-1992; Echographers:
David Beers; Sandra R. Sall; Photographers: Lawrence Disney, COA; Martin Lopez,
COT, 1989-1990; Ophthalmic Pathologist: Robert Keyser, MD, 1989-1993. Hermann Eye Center, Houston, Tex: Principal Investigator:
Richard S. Ruiz, MD; Clinic Coordinators: Dalia Vargas; Maria DeLaGarza, 1988-1992;
Robert W. Johnson, COA, RDO, 1992-1993; Walter Kohn, MS, 1987-1989; Georgia
Triplett, OA, 1992; Ophthalmologists: Graham P. Avery, MD; Judianne Kellaway,
MD; H. Michael Lambert, MD; Paul C. Salmonsen, MD; Debra J. Shetlar, MD, 1993-1994;
Radiation Oncologists: Nora A. Janjan, MD; Joseph Kong, MD, 1987; William
Morrison, MD, 1987-1996; Radiation Physicist: Otto Zeck, PhD; Echographers:
Thomas C. Prager, PhD; Yali Zou, MD; Photographers: Charles B. Smith; Teddy
J. Horton, 1987-1989. Midwest Eye Institute, Indianapolis,
Ind: Principal Investigator: John T. Minturn, MD; Clinic Coordinators:
Donna J. Agugliaro, RN, BSN; Margaret B. Kirby, RN, 1989-1992; Kimberly A.
Sharkey, CST, 1989; Ophthalmologists: Ronald T. Martin, MD; William R. Nunery,
MD; Radiation Oncologist: Peter Garrett, MD; Radiation Physicists: Ronald
E. Berg, PhD; John Kent, MS; Photographers: Carolyn S. Lamb; William T. Bussell,
1995; Linda Huber, CRA, 1989-1995; Thomas C. Meador, 1997; Kenneth D. Phelps,
1995-1996; Ophthalmic Pathologist: Jose M. Bonnin, MD. The University of Iowa, Iowa City: Principal Investigator: Thomas A.
Weingeist, MD, PhD; Clinic Coordinators: Connie Fountain, COT; Marcia Griffin;
Ophthalmologists: H. Culver Boldt, MD; Keith D. Carter, MD; Jeffrey A. Nerad,
MD; Edwin M. Stone, MD, PhD; Christopher F. Blodi, MD, 1987-1992; Radiation
Oncologists: David H. Hussey, MD; Antonio Vigliotti, MD, 1987-1991; B-Chen
Wen, MD, 1991-2000; Radiation Physicists: Womah S. Neeranjun, MS, 1994-1997;
Edward Pennington, ScM, 1987-2000; Echographers: Tom Fisher; Laura Warner;
Karl C. Ossoinig, MD, 1986-1997; Photographers: Edward Heffron, MA; Stefani
V. Karakas, CRA; Randall E. Verdick; Ophthalmic Pathologist: Robert Folberg,
MD, 1986-2000; Following Oncologists: Gerald H. Clamon, MD; Susan A. Kambhu,
MD, 1996-1998. Estelle Doheny Eye Foundation, Los Angeles,
Calif: Principal Investigators: A. Linn Murphree, MD; Peter E. Liggett,
MD, 1986-1991; Stephen J. Ryan, MD, 1985-1986; Clinic Coordinators: Margaret
Padilla; A. Frances Walonker, CO, COMT; Beth Quillen-Thomas, COMT, 1987-1991;
Ophthalmologists: |
