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The COMS Randomized Trial of Iodine 125 Brachytherapy for Choroidal Melanoma, III: Initial Mortality Findings
COMS Report No. 18
The Collaborative Ocular Melanoma Study Group
Arch Ophthalmol. 2001;119:969-982.
ABSTRACT
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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 -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.
INTRODUCTION
CHOROIDAL melanoma, a primary intraocular cancer, has the potential
to extend locally through the scleral wall and into the orbit and to metastasize
to the liver and other extraocular sites. No effective treatment has been
found to date for metastatic choroidal melanoma.1-4
Death typically occurs within months after metastasis is detected clinically.4-5 Thus, the goal is to treat choroidal
melanoma while it is confined to the eye. For nearly 100 years, enucleation
was the only treatment for choroidal melanoma that was believed to protect
the patient from metastasis and death. Enucleation can be performed by most
ophthalmologists and, thus, is widely available. It remains the accepted treatment
for large choroidal melanoma.6-8
However, alternatives to enucleation have been deemed desirable, particularly
for smaller choroidal melanoma. The benefits of an eye-conserving treatment
include retention of the eye and some vision and perceived cosmetic benefits
that may result in better quality of life. In addition, removal of an eye
that occasionally, albeit rarely, has been misdiagnosed as containing choroidal
melanoma may be avoided. Moreover, choroidal melanoma that remains small in
size is believed by most ophthalmologists and oncologists to have little potential
for metastasis to extraocular sites.9-11
However, despite technical advances in the development of alternative treatments,
evaluations of eye-conserving treatments with respect to mortality or metastatic
tumor spread only recently have provided data from long-term follow-up of
patients.12-14
In addition, eye-conserving treatments may be considerably more expensive
than enucleation because of the facilities, materials, or expertise required
to administer them or because of more frequent clinical examinations to monitor
the tumor for regrowth after treatment.
The interest in alternatives to enucleation of eyes with choroidal melanoma
was heightened in the 1970s by an analysis of data presented by Zimmerman
and McLean et al15-17
that purported to show, contrary to expectation, that enucleation increased
the risk of tumor metastasis. This hypothesis and the discussion it provoked18-21 emphasized
the need for long-term follow-up studies of both enucleation and alternative
treatments. At that time, radiotherapy was considered the best alternative
to enucleation. Several isotopes and delivery systems had been developed and
were in use for treatment of choroidal melanoma in the United States and elsewhere.
By the early 1980s, some ophthalmologists and radiation oncologists
advocated radiotherapy as the preferred treatment for choroidal melanoma when
the tumor was not so large that enucleation was the only reasonable approach
or so small that the diagnosis of choroidal melanoma could not be made reliably
without observation of tumor growth during clinical follow-up.22-24
However, with only short-term survival data available, many ophthalmologists
were concerned that the patient's life would be shortened by any treatment
that did not include removal of the eye.
In 1983 and 1984, the National Eye Institute of the National Institutes
of Health, Bethesda, Md, sponsored several meetings of ophthalmologists and
others interested in the treatment of choroidal melanoma, including proponents
of radiotherapy, to evaluate and summarize the survival data available for
patients treated with radiotherapy, to compare them with similar data from
patients treated with enucleation, and to reach a consensus on the design
of studies judged necessary to evaluate radiotherapy. Most ophthalmologists
and oncologists who participated in these meetings believed that only a multicenter
clinical trial in which patients with this rare cancer would be assigned randomly
to eye-conserving radiotherapy or enucleation and followed for a minimum of
5 years for mortality would settle the controversy.
Thus, the Collaborative Ocular Melanoma Study (COMS) was designed primarily
to compare radiotherapy with enucleation with respect to mortality among the
subset of patients with choroidal melanoma for whom radiotherapy would be
considered an acceptable treatment by the ophthalmologist and patient if it
provided survival rates comparable to enucleation. When the COMS was designed
in 1985, the 2 most widely used methods of radiotherapy for choroidal melanoma
were charged particles22, 24 and
brachytherapy by means of episcleral plaques to which radioactive material
was affixed.23, 25-27
Several factors were considered in the selection of a radioactive plaque and
iodine 125 for radiation delivery in this COMS trial, as discussed elsewhere.28-29
Accrual of patients to the COMS clinical trial of 125I brachytherapy
began in February 1987 and was completed on July 31, 1998, after the number
of patients required to meet the primary objectives of the trial had enrolled.
The purpose of this report is to present mortality findings after a minimum
follow-up of 2 years and a maximum follow-up of 13 years of the patients in
the 2 treatment arms. Initial findings from a parallel study of health-related
quality of life30 will be available within
the next 2 years. Initial findings from a randomized trial of preenucleation
external beam irradiation for large choroidal melanoma, also conducted by
the COMS Group, were published in 1998.8, 31-32
PATIENTS AND METHODS
Descriptions of many aspects of the COMS design and methods have been
published previously.8, 31-40
The COMS Manual of Procedures41
and the COMS Forms Book42
are available.
The Data and Safety Monitoring Committee appointed by the National Eye
Institute director 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 patient enrollment at individual centers.
INITIAL EVALUATION
Patients with suspected choroidal melanoma were referred by their ophthalmologists
to 1 of 43 COMS clinical centers in the United States and Canada for confirmation
of the diagnosis and evaluation of eligibility for either of 2 COMS randomized
trials of radiotherapy. Details of examinations and methods of patient evaluation
and data collection used in one or both COMS clinical trials have been reported
elsewhere.8, 31-32,37-40
In brief, a medical and ocular history was elicited before the patient underwent
a detailed ophthalmic examination by a COMS ophthalmologist. The ophthalmic
examination included ophthalmoscopic and biomicroscopic examination of the
tumor and the fundus of each eye. 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 in accord with a standard
protocol.41 Standardized A-scan and contact
B-scan echography were performed.37 Wide-angle
color photographs and frames during fluorescein angiography were obtained
of all tumor margins, whenever possible, and of the macula and optic disc
of both eyes.
As part of the ophthalmoscopic examination, the ophthalmologist estimated
the apical height and the longest basal diameter of the tumor, taking account
of both clinical observations and local measurements from echograms. The ophthalmologist
also provided a detailed description of tumor location based on distances
from landmark intraocular structures, with particular attention to location
relative to the optic disc to assess eligibility for enrollment.
Patients judged to be eligible based on ophthalmologic examination and
medical history were referred to the local COMS radiation oncologist for discussion
of radiation issues. The radiation oncologist, a medical oncologist, or an
internist performed a cancer-oriented physical examination that included a
detailed medical history, laboratory studies, and anterior-posterior radiography
of the chest. A computed tomographic scan, magnetic resonance images, or biopsy
of the liver or other organs was required by the COMS protocol only when necessary
to rule out metastatic melanoma or other neoplasms following defined abnormalities
in tests of liver function or other suspicious findings from the physical
examination.
Echograms were forwarded to the COMS Echography Center (Mars Hill, NC)
where study personnel reviewed them for consistency with the diagnosis of
choroidal melanoma and evidence of extrascleral extension, measured the apical
height of the tumor, and classified configuration, location, and internal
reflectivity of the tumor. Wide-angle photographs and fluorescein angiograms
were forwarded to the COMS Photograph Reading Center (Iowa City, Iowa) for
confirmation of 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 AND EXCLUSION CRITERIA
The choroidal melanoma had to be 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.)
Patients with peripapillary tumors, ie, 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. Whenever the ocular media were temporarily too opaque to assess
eligibility, to make the necessary baseline observations, or to estimate dimensions
that would be necessary for planning 125I brachytherapy, at the
option of the patient and ophthalmologist, a final decision regarding eligibility
and enrollment could be postponed until sufficient clarity was achieved; otherwise,
the patient was deemed ineligible.
Eligible patients had unilateral primary choroidal melanoma; were aged
21 years or older; 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 and other primary or metastatic cancers; 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 able to return for posttreatment follow-up examinations. In
a few instances, patients who had received a cancer diagnosis in the distant
past, were documented to be free of recurrence, and were in good health apart
from the choroidal melanoma were permitted to enroll in the clinical trial
after consultation with and approval by the principal radiation oncologist
or the designated medical oncologist. Otherwise, patients who had a history
of cancer other than noninvasive nonmelanotic skin cancer or carcinoma in
situ of the uterine cervix were ineligible. Previous treatment for choroidal
or ciliary body melanoma in either eye, treatment of any condition secondary
to the tumor, or fine-needle aspiration biopsy of the melanoma rendered a
patient ineligible for the clinical trial. Patients with extrascleral tumor
extension 2.0 mm or thicker detected during echography or clinical examination;
diffuse, ring, or multifocal tumors; or tumors judged to be predominantly
ciliary body melanoma were ineligible. Patients using immunosuppressive therapy
that could not be discontinued indefinitely also were ineligible.
ENROLLMENT AND TREATMENT ASSIGNMENT
Eligible patients who gave signed consent were enrolled by means of
a telephone call from the local clinic coordinator and ophthalmologist to
the COMS Coordinating Center (Baltimore, Md). During the call, the patient
was registered, eligibility was reviewed, and the next treatment assignment,
enucleation or 125I brachytherapy, was selected by computer from
an encoded electronic file of treatment assignments prepared by Coordinating
Center personnel and communicated to the clinical personnel. Randomly permuted
blocks of assignments of randomly selected sizes were used to construct the
treatment assignment files. A separate file of treatment assignments was maintained
for each clinical center for each clinical trial. Official enrollment of the
patient took place when the treatment assignment was communicated by Coordinating
Center personnel to 2 members of the enrolling clinical center staff.
125I BRACHYTHERAPY PROTOCOL
The COMS Radiation Therapy and Physics Committee designed a standard
set of episcleral plaques made of gold alloy and patterned after individually
fabricated plaques.27, 43 Sets
of plaques that were 12, 14, 16, 18, and 20 mm in diameter were fabricated
centrally (Trachsel Dental Studio, Rochester, Minn) or locally to the same
standards after approval by the Radiation Therapy and Physics Committee.41 The soft plastic seed carrier was cemented to the
plaque so that the 125I seeds were placed in evenly spaced slots
arranged in concentric rings with 1 mm of carrier between the seeds and the
sclera. The size of the plaque was selected to provide a 2- to 3-mm margin
beyond the base of the tumor; thus, the size of the plaque was 4- to 6-mm
greater than the maximum basal diameter of the tumor. For tumors near the
optic nerve, notched plaques of the same design or plaques with the lip removed
adjacent to the optic nerve were permitted.
For COMS purposes, the dosimetry recommended by Task Group 43 of the
American Association of Physicists in Medicine Radiation Therapy Committee
was followed.44 Seeds were assumed to be point
sources without anisotropy. The effects of the gold plaque on scatter and
attenuation were ignored, as was the shielding owing to the plaque rim. The
plastic insert was assigned water equivalent absorption. Additional details
are provided in the COMS Manual of Procedures.41
For choroidal melanoma 5 mm or greater in apical height, the dose was
prescribed to the apex of the tumor. For tumors 2.5 to 4.9 mm high at the
apex, the prescription point was 5 mm from the interior surface of the sclera.
The protocol dose to the prescription point was 85 Gy, delivered at a rate
of at least 0.42 Gy per hour but no more than 1.05 Gy per hour. Thus, the
85 Gy isodose surface passed through the prescription point, encompassed the
entire tumor, and extended at least to the edge of the gold plaque.
The COMS protocol required that each 125I seed be assayed
separately using an ionization chamber that had been calibrated by the local
radiation physicist with an 125I seed calibrated at the National
Institute of Standards and Technology (Gaithersburg, Md) or at an accredited
dosimetry calibration laboratory for the type of 125I seed used
locally (model 6711 or 6702). Records of the constancy of the chamber factor
were maintained for periodic review by physicists from the Radiological Physics
Center (Houston, Tex).
Doses to critical ocular structures were calculated by the local COMS
radiation oncologist and physicist on the basis of measurements, retinal drawings,
and dimensions provided by the examining ophthalmologist. For COMS purposes,
the dose to the sclera at the tumor base was estimated at a point on the central
axis of the plaque 1 mm from the surface of the plaque. The dose to the optic
nerve was calculated at the center of the optic disc; the dose to the macula
was calculated at the foveola. The dose to the retina opposite the tumor was
calculated 22 mm from the scleral surface at the base of the tumor as measured
along the diameter of the globe that passed through the tumor apex.
Prior to approval to enroll patients in the COMS trial, the dosimetry
software and calibration facilities at each participating center were tested,
and adherence to the COMS protocol was documented for 1 or more test cases.
In addition, the local COMS team of ophthalmic surgeon, radiation oncologist,
and radiation physicist and the local radiation safety officer were required
to collaborate in the preparation and application of an 125I plaque
to a non-COMS patient. For each COMS treatment, the following data were submitted
to the Radiological Physics Center for review: all measurements of tumor location
and dimensions; intraocular distances between the tumor and critical structures;
a diagram or photograph of the plaque that showed the placement of the 125I seeds and the distance from the seeds to the surface of the applicator;
seed strength in units of air Kerma Strength and the date of assay; apparent
seed activity in units of MCi and the date of assay; number of seeds used;
total length of implant; and dose distribution perpendicular to the plaque
through the tumor apex, with the tumor outlined on the distribution to show
the tumor thickness and basal dimensions. Dosimetry was calculated independently
at the Radiological Physics Center. Local dosimetry calculations were corrected
as appropriate after confirmation with local COMS personnel. Protocol adherence
was assessed by Radiological Physics Center personnel. In addition, all radiotherapy
documentation was forwarded to the COMS principal radiation oncologist who
reviewed the material and provided a final assessment of adherence to the
brachytherapy protocol.
Procedures for plaque placement and removal have been described and
illustrated elsewhere.41, 45 Transparent
templates were available in the same sizes as the gold shields and were used
to facilitate localization and subsequent placement of the radioactive plaque.
Ocular and systemic complications observed during placement or removal of
the radioactive plaque and during examinations in the immediate postoperative
period were reported on standard forms that were sent to the Coordinating
Center.
The COMS protocol specified that 125I brachytherapy be completed
within 4 weeks after enrollment of the patient. In those cases in which plaque
placement was delayed by more than 4 weeks, the ophthalmologist was required
to repeat the initial ophthalmologic and echographic examinations and to communicate
to the radiation oncologist and physicist any changes in tumor dimensions
and other intraocular measurements so that corrections could be made to the
dosimetry calculations. Complications and observations at the time of plaque
placement and removal, dosimetry data, and results of evaluations at the Radiological
Physics Center and by the principal radiation oncologist were reported on
standard forms42 sent to the Coordinating Center.
ENUCLEATION PROTOCOL
The COMS protocol specified that enucleation of eyes so assigned take
place within 4 weeks after enrollment. Selection of general or local anesthesia
was based on patient status, preferences of the patient and surgeon, and local
circumstances. After a 360° limbal peritomy and detachment of the conjunctiva
and the Tenon capsule, the surgeon inspected each quadrant for evidence of
extraocular extension. Whenever extraocular tumor was present, the tumor was
dissected beyond all visible margins; transection of any portion was avoided.
Recti muscles, and oblique muscles whenever indicated, were cut from insertions
with as little manipulation as possible; the optic nerve was cut posterior
to the globe beyond any visible tumor extension along the nerve. After removing
the eye, the surgeon closed peripheral rents in the Tenon capsule and inserted
a nonmetallic implant. The posterior opening in the Tenon capsule was not
closed routinely. The surgeon performed a tenonectomy whenever tumor was visible
in the sclera or extraocular extension was observed.
Intraoperative and immediate postoperative ocular and systemic complications
were reported on standard forms.42 After the
orbital tissues had healed, patients were referred to an ocularist for construction
and fitting of a prosthesis.
Enucleated eyes were processed either locally or centrally for central
histopathologic assessment at the COMS Pathology Center (Madison, Wis); the
procedures have been reported.34-36
Cell type was coded by members of the Pathology Review Committee using the
modification of the Callender classification developed at the Armed Forces
Institute of Pathology (Washington, DC).46
A detailed report of histopathologic findings was sent to the clinical center
after central assessment of each ocular tumor.
PATIENT FOLLOW-UP
Patients were examined as necessary for clinical care during the postoperative
period; they were scheduled for an examination for data collection purposes
no later than 6 weeks after surgery. Subsequent clinical examinations for
data collection purposes were scheduled 6 months after enrollment and at 6-month
intervals thereafter until the 5-year examination. During the next 5 years,
examinations at annual intervals were required; examinations at the midpoint
between annual examinations were optional. Whenever a clinical examination
was not conducted between annual examinations, the patient was contacted by
telephone to ascertain current health status. As a patient approached the
10-year anniversary of enrollment, he or she was asked to consent to continued
follow-up examinations and data collection by COMS personnel. Patients who
agreed continued to be followed at annual examinations and received either
an examination or a telephone interview at the midpoint between annual examinations.
At each scheduled follow-up examination of patients in the 125I brachytherapy arm, the ophthalmologist conducted a detailed examination
that included assessment of tumor margins for evidence of expansion. Standardized
A-scan and contact B-scan echography were performed to ascertain current apical
height of the tumor and to detect any extrascleral tumor growth. Suspected
growth of choroidal melanoma during follow-up after the immediate posttreatment
period mandated more frequent follow-up examinations. Treatment failure, as
documented by growth of the tumor, extrascleral extension, or severe ocular
pain, was managed at the discretion of the ophthalmologist. The reason for
treatment failure and any additional treatment were reported to the Coordinating
Center.
For each patient whose eye had been enucleated, the ophthalmologist
examined the socket and eyelids for local tumor recurrence. The fit of the
prosthesis was checked and the patient was referred to an ocularist for modifications
as necessary. The fellow eyes of all patients were examined for any new ophthalmologic
problems. The best-corrected visual acuity of the fellow eye and tumor-containing
eye when present was measured following the same protocol as at baseline.
A cancer-oriented physical examination was performed; blood tests and chest
radiography, and other tests, as required, were performed to judge whether
distant metastasis of the melanoma had occurred.
Documentation of metastasis, including reports of findings from diagnostic
procedures and biopsy slides when available, was provided for central review.
Deaths of patients were reported promptly, either by mail or telephone pending
receipt of the death certificate, and logged immediately at the Coordinating
Center. In May 1997, a search of the National Death Index database (National
Center for Health Statistics, Department of Health and Human Services, Rockville,
Md) was undertaken to ascertain the vital status of a few patients who had
been reported to be lost to follow-up by the responsible clinical center personnel.
Information concerning events prior to death was evaluated by the Mortality
Coding Committee to ascertain whether metastatic melanoma was present at the
time of death. The committee members were masked to the treatment arm of each
deceased patient. Documentation of the course of the final illness, including
laboratory and diagnostic studies and clinical observations, was obtained
from the local caregivers by local COMS clinical personnel and forwarded to
the Coordinating Center for review and masking of information that would identify
the patient or reveal the initial treatment for choroidal melanoma. Whenever
possible, autopsy and biopsy slides of suspected malignancies were obtained
for central review. Metastatic melanoma was diagnosed only when confirmed
by autopsy, biopsy, or cytology findings. A detailed description of the procedures
followed by the Mortality Coding Committee has been reported elsewhere.39
STUDY MONITORING
Because it was judged unlikely that a similar randomized trial for choroidal
melanoma patients would be carried out by the COMS Group or other investigators,
particular attention was given to assuring that the COMS was designed and
conducted in a manner to produce data of high quality. Quality assurance activities
focused on diagnostic accuracy, enrollment of eligible patients, centralization
of random treatment assignment and other key functions in specialized resource
centers and expert committees, adherence to treatment protocols, completeness
of patient follow-up, and careful review of all records relating to cause
of death.
The COMS Quality Assurance Committee was responsible for quality assurance
activities and for monitoring protocol adherence and data quality. Each resource
center was represented by a member on the Quality Assurance Committee and
had specific responsibilities for data quality, including training and certification
of COMS personnel in their study roles and in data recording and submission
procedures. Deficiencies in materials or data submitted were called to the
attention of the COMS protocol monitor who chaired the Quality Assurance Committee.
Following an initial site visit to each center by members of the Executive
Committee, site visits at 2- to 3-year intervals, or more frequently when
indicated, were made to each clinical center by personnel from the Coordinating
Center. During these site visits, local COMS operations were observed, protocol
adherence was reviewed, and samples of data reported to the Coordinating Center
were compared with findings in patient charts. Site visits to clinical centers
by personnel located at other COMS resource centers were scheduled as indicated
to solve problems, train new COMS personnel, or calibrate replacement equipment
and facilities. At least 1 follow-up site visit was made to each resource
center approximately 5 years after the initial visit by members of the Executive
Committee or Data and Safety Monitoring Committee or by outside experts.
Beginning in September 1987, an independent Data and Safety Monitoring
Committee reviewed accumulated data twice each year, with at least 1 review
each year taking place at a full committee meeting. Initially, the committee
reviewed mortality data from the 2 treatment groups combined; all other data,
including complications, were reviewed with the treatment arm identified.
At annual meetings in 1990, 1992, 1995, and 1997, the committee reviewed mortality
data presented separately by treatment arm. At the time of the November 1997
review when the minimum accrual goal had been met, the committee recommended
that accrual continue until July 31, 1998, that no additional patients be
enrolled after that date but that follow-up of all patients continue in order
to increase statistical power. This recommendation was made after reviewing
information on survival by treatment arm and several analyses of the conditional
likelihood of future changes in survival trends in each treatment arm. At
the November 1999 meeting, the committee recommended that follow-up continue
until the last patient enrolled was eligible for a 5-year examination and
that the earliest patients enrolled be followed clinically for a maximum of
15 years, with the final study examinations to take place at the annual examinations
between August 1, 2002, and July 31, 2003. At the December 13, 2000, meeting,
with the 5-year survival outcome known for more than 80% of all patients,
the committee approved publication of current mortality findings and reaffirmed
the recommendation made in November 1999 that follow-up of patients continue.
SAMPLE SIZE, DATA MANAGEMENT, AND DATA ANALYSIS
A range of acceptable sample sizes was developed during the design phase
of the trial.33, 41 Sample size
estimates were based on the assumption that 70% of the patients assigned randomly
to the enucleation arm would be alive 5 years after enrollment47
and that the study should be able to detect or rule out a relative difference
in 5-year all-cause mortality of 25% (eg, 30% vs 22.5% or 30% vs 37.5%). The
maximum target sample size of 2400 patients was based on a type I ( )
error of .01 (2-sided), a type II ( ) error of .10 (ie, 90% power), and
a projected 5-year rate of loss to follow-up for vital status of 5% of patients
enrolled. The minimum acceptable sample size of 1250 patients was designed
to provide 80% power and a type I error of .05, typical choices for randomized
trials of treatments for other cancers, with no change in the other assumptions.
Data from clinical evaluations and from review of echograms, photographs,
sections of enucleated eyes, and status at death were recorded on standard
forms42 that were forwarded to the Coordinating
Center for transcription to computer files. Automated and manual edits of
the data for completeness, consistency, and protocol adherence; integration
of all data for each patient; and data analysis and reporting were the responsibility
of the Coordinating Center. Data received by September 30, 2000, have been
included in this analysis.
All patients were analyzed with the treatment arm to which they were
assigned randomly at time of enrollment, regardless of subsequent findings
or treatment received ("intent-to-treat" analysis strategy). The Wilcoxon
rank sum test48 has been used to compare distributions
of continuous variables. The  2 test for trend in ordered categories49 was used to compare distributions of categorical
variables in 3 or more qualitatively or quantitatively ordered categories.
The 2 test for homogeneity48
was used to compare dichotomous distributions and distributions in which the
categories have no inherent qualitative or quantitative order. Time to death
was estimated using the product-limit method of Kaplan and Meier.50 Survival rates by treatment arm were compared using
the log-rank test51-52; no adjustment
has been made to account for 5 reviews of outcome data by the Data and Safety
Monitoring Committee. All statements of probability (P
values) are 2-sided. Patients who refused follow-up in the COMS beyond the
10-year examination were censored following that examination. For analysis
of time to death with metastatic melanoma, deceased patients without histopathologically
confirmed metastatic melanoma were censored at time of death. Patients not
reported as deceased and not discovered to have died during the May 1997 search
of the National Death Index database were assumed to be alive as of the cutoff
date for this analysis. The proportional hazards model of Cox53
has been used to adjust for the simultaneous effects of baseline covariates
to account for minor imbalances between treatment arms at enrollment. SAS
computer software (SAS Institute, Cary, NC) was used for proportional hazards
analyses and for calculating risk ratios and confidence intervals (CIs).
RESULTS
When accrual ended in July 1998, 1317 patients had enrolled: 46% of
2882 patients with choroidal melanoma who were judged by the local study investigators
to be eligible for the trial, and 26% of all 5046 patients reported to have
choroidal melanoma of eligible size. Reasons for ineligibility and other reasons
patients did not enroll have been reported elsewhere.40
The most frequently reported reasons for ineligibility were tumor proximity
or contiguity to the optic disc, previous diagnosis of another primary cancer,
and tumor location predominantly in the ciliary body.
Of the 1317 patients who enrolled, 660 were assigned randomly to enucleation,
and 657 were assigned to 125I brachytherapy. After all baseline
data had been received at the Coordinating Center, 12 patients (7 assigned
to enucleation and 5 assigned to 125I brachytherapy) were discovered
to have been ineligible for the clinical trial based on strict application
of COMS criteria. Seven of these 12 patients (4 assigned to enucleation and
3 assigned to brachytherapy) had an earlier diagnosis of cancer. One patient
assigned to brachytherapy had earlier photocoagulation to a retinal detachment
associated with the tumor; another was receiving corticosteroids at enrollment.
One patient assigned to enucleation had extrascleral extension greater than
2 mm visible on echogram; another had visual acuity in the fellow eye worse
than 20/200. The remaining patient assigned to enucleation was judged ineligible
based on central review of echograms and photographs and was diagnosed to
have a choroidal neovascular lesion rather than choroidal melanoma. The data
from each of the 12 patients found to be ineligible after enrollment have
been analyzed with those of the treatment group to which the patient was assigned
at time of enrollment.
The numbers of patients in each treatment group by length of mortality
follow-up through September 30, 2000, are given in Table 1. All patients had been followed for vital status for 2 years
or longer; 1274 (97%) had been followed for at least 3 years. Based on time
since enrollment, 1072 patients (81%) were eligible for 5 or more years of
mortality follow-up; 416 patients (32%) were eligible for 10 or more years
of follow-up.
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Table 1. Patients Followed for Mortality by Time and Treatment Group
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BASELINE CHARACTERISTICS
Sociodemographic characteristics of patients, characteristics of choroidal
melanoma, and ocular status at time of enrollment are given in Table 2, Table 3, Table 4, Table 5, and Table 6.
Mean ages of patients at the time of enrollment were 60.4 years and 59.1 years
for those assigned to enucleation and brachytherapy, respectively (P = .13). The treatment arms were well balanced on all other baseline
characteristics.
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Table 2. Patients With Specified Sociodemographic Characteristics at
Baseline
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Table 3. Patients With Specified Tumor Characteristics at Baseline
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Table 4. Patients by Ophthalmologic Assessment of Location of Choroidal
Melanoma
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Table 5. Patients by Tumor Characteristics
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Table 6. Patients by Ocular History and Status at Baseline
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Most patients enrolled within 1 month of the initial diagnosis of choroidal
melanoma (Table 3); the median
interval from diagnosis to enrollment was 20 days. However, 82 patients assigned
to enucleation (13%) and 105 patients assigned to brachytherapy (16%) enrolled
6 months or longer after diagnosis. In each treatment arm, 45% of the tumors
were 2.5 mm to 4.0 mm in apical height (Table 3). The mean apical height of the tumors was 4.8 mm; mean
length of the longest diameter of the tumor base was 11.4 mm. Among 728 patients
(55%) the entire tumor was located posterior to the equator; the anterior
tumor boundary extended into the ciliary body in the eyes of only 143 patients
(11%) (Table 4). In 632 patients
(48%) the tumor apex was in the quadrant temporal to the fovea; the tumor
apex was in the quadrant nasal to the fovea for only 159 patients (12%). The
median distance between the closest tumor margin and the edge of the optic
disc was 4.0 mm; 216 patients (16%) had choroidal melanoma that extended closer
than 2.0 mm to the proximal edge of the optic disc. A larger percentage of
the patients had choroidal melanoma located over or close to the center of
the foveal avascular zone: 190 (14%) over the center, and 345 (26%) within
2.0 mm of the center (Table 4).
The median distance between the tumor and the center of the foveal avascular
zone was 3.0 mm.
Features of the tumors are displayed in Table 5. A dilated feeder vessel to the tumor was visible at baseline
in 46 eyes (3%); a nonrhegmatogenous retinal detachment associated with the
tumor was reported for 720 eyes (55%), and a rhegmatogenous detachment for
6 eyes (<1%). Most of the tumors (1014 [77%]) were dome shaped; only 207
(16%) were collar-button shaped. Internal reflectivity was low, low-medium,
or medium for 1111 tumors (84%). Epibulbar pigment was reported by the ophthalmologist
for 13 patients (1%). The ophthalmologist reported drusen on the tumor surface
for 91 (25%) of 350 patients enrolled by 1990 when reporting of this observation
was halted (data not shown).
Among the study eyes (tumor-containing eyes), 255 (19%) had other vision-limiting
or vision-threatening conditions diagnosed in the past (Table 6). The most frequently reported condition was cataract in
165 study eyes (13%). Among fellow eyes, 227 (17%) had conditions that limited
or threatened vision; cataract also was the most common condition in fellow
eyes, accounting for 166 fellow eyes (13%). Nevertheless, almost all patients
were phakic in both eyes (Table 6).
As given in Table 6, more
than two thirds of patients had excellent visual acuity in the fellow eye;
only 23 patients had fellow eye visual acuity worse than 20/50. Although nearly
one third of patients had a best-corrected visual acuity of 20/20 or better
in the study eye at baseline, visual acuities spanned a wide range, with 64
patients (5%) having visual acuity worse than 20/500 (10/250) in the study
eye.
Although patients with coexisting medical conditions expected to lead
to death within 5 years, as judged by the examining physician, were excluded,
more than two thirds of participating patients had 1 or more coexisting medical
conditions at the time of enrollment (Table
7). Cardiovascular and circulatory conditions were the most common,
with 290 patients in the enucleation arm (44%) and 256 patients in the brachytherapy
arm (39%) reporting such conditions. The most common finding during baseline
examination of the skin was cutaneous moles, reported for 33% of the patients
in the enucleation arm and for 30% of the patients in the brachytherapy arm
(data not shown). Fewer than 20 patients in each treatment arm (<3%) were
reported to have vitiligo, subcutaneous nodules, or unusual pigmentation.
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Table 7. Patients With History of Specified Medical Conditions at Baseline
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Nearly two thirds of the participating patients had 1 or more blood
relative who had cancer (data not shown). Fourteen patients, 5 in the enucleation
arm and 9 in the brachytherapy arm, reported having a relative who had been
diagnosed with choroidal melanoma. Sixty-seven patients, 37 assigned to enucleation
and 30 assigned to brachytherapy, reported a relative who had cutaneous melanoma.
TREATMENT AND TREATMENT PROTOCOL ADHERENCE
Of the 657 patients assigned to 125I brachytherapy, 650 were
treated in the manner assigned and within the time limits specified by the
COMS protocol. One patient delayed brachytherapy for 7 months; another patient
delayed brachytherapy until after fine-needle aspiration biopsy and was treated
at a center not participating in the COMS. A third patient who was discovered
to have metastasis soon after enrollment was observed without treatment until
death 6 months later. After random assignment to brachytherapy, 2 patients
decided to undergo enucleation, and 1 decided to have teletherapy. For 1 additional
patient, the COMS surgeon judged during surgery that a plaque could not be
placed to cover the tumor base; subsequently, the eye was removed.
Of the 660 patients assigned to enucleation, 646 were treated promptly
as assigned. One patient delayed enucleation for 14 months until the tumor
had grown and the eye had become blind and painful. One patient initially
refused enucleation; he returned to the clinical center nearly 6 years after
enrollment to have the eye removed. One additional patient refused enucleation
after randomization and was observed. Another patient did not undergo enucleation
after a misdiagnosis of choroidal neovascularization was discovered during
central review of echograms and photographs. After random assignment to enucleation,
7 patients decided to receive brachytherapy; 2, proton beam radiation; and
1, cryotherapy and eye-wall resection outside the COMS. Thus, all but 21 (1.6%)
of 1317 patients were treated promptly as assigned at time of enrollment.
Furthermore, 2 of these 21 patients received the assigned treatment after
an initial delay; 1 additional patient had the assigned treatment after a
prolonged delay, and 1 received the assigned treatment at a center not participating
in the COMS.
Table 8 summarizes 125I brachytherapy and dosimetry for the 650 patients who were so assigned
and treated promptly. Summary distributions are presented separately by the
location of the prescription point. The values represent the minimum (0 percentile);
lower bound of the central 90% (5th percentile); lower quartile (25th percentile);
median (50th percentile); upper quartile (75th percentile); upper bound of
the central 90% (95th percentile); and maximum (100th percentile) of each
distribution. As expected, the median number of 125I seeds used
for smaller tumors (prescription point located 5 mm from the inner surface
of the sclera) was less than for larger tumors (prescription point at tumor
apex): 13 vs 20. The distributions of the duration of the implant were similar,
apart from a small shift of 4 to 6 hours in the median and the 25th and 75th
percentiles of the distributions. The extreme duration of 458 hours resulted
from an initial miscalculation of the dose rate that was discovered after
the radioactive plaque had been inserted. Two patients in each subgroup had
a dose rate lower than that prescribed by the brachytherapy protocol; for
3 patients, 1 whose prescription point was 5 mm from the sclera and 2 with
the prescription point at the tumor apex, the dose rate was higher than that
specified by the protocol. In both subgroups, more tumors received a radiation
dose that was lower than that specified by the COMS protocol than received
a dose that was greater than protocol (Table 8). In the subgroup of smaller tumors (prescription point
5 mm from the inner surface of the sclera), undertreatment typically resulted
from use of the tumor apex as the prescription point
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Table 8. Description of Iodine 125 Brachytherapy by Location of Prescription
Point
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Central reviews of dosimetry and protocol adherence were completed for
all 650 eyes treated with brachytherapy. Personnel at the Radiological Physics
Center judged the size of the plaque used to be incorrectly selected in 17
(3%) of the cases, with 4 cases ruled to have minor deviations (ie, plaque
diameter more than 6.0 mm but not more than 8.0 mm greater than the longest
basal diameter of the tumor) and 13 judged to be major deviations (plaque
diameter less than 4.0 mm or more than 8.0 mm greater than the longest basal
diameter of the tumor). With respect to dose to the prescription point, 17
minor deviations (dose delivered differed by more than 5% but no more than
10% of the target dose of 85 Gy) and 21 major deviations were reported. Dose
rates outside the range prescribed by the protocol were rare; only 9 were
noted during central review. Overall, 592 tumors (91%) were treated per protocol
specifications. Of the remainder, a minor deviation was noted for 24 (4%)
and a major deviation for 33 (5%). In the remaining case, the central seed
positions were left unfilled. Although the COMS protocol specified an even
distribution of sources, uneven distribution was not defined specifically
as a protocol deviation. Nonetheless, the higher scleral dose relative to
the prescription dose was noted as an anomaly during central review.
PERIOPERATIVE AND POSTOPERATIVE COMPLICATIONS
Table 9 summarizes complications
and observations reported at the time of enucleation surgery or at the time
of plaque application or removal. For 2 patients in the enucleation arm, extrascleral
tumor extension 2 mm or thicker was observed at the time of surgery. For 5
additional patients, tumor extension to the scleral surface or extrascleral
extension less than 2-mm thick was discovered at the time of surgery; a tenonectomy
was performed for these 5 patients and for 3 others for other reasons. Other
complications applicable to patients in both treatment arms were reported
with similar frequency.
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Table 9. Patients With Intraoperative and Immediate Postoperative Complications
and Observations*
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Among brachytherapy patients, the most common complications during the
first 5 years after treatment were loss of visual acuity38
and growth of the tumor and other indications that led to enucleation. Among
all patients treated with 125I brachytherapy, regardless of baseline
visual acuity, the 5-year cumulative rate and 95% CI for visual acuity of
20/200 or worse in the study eye at 2 consecutive examinations was 63% (95%
CI, 59%-68%); for visual acuity of 5/200 or worse, the rate was 45% (95% CI,
41%-50%). By 5 years after 125I brachytherapy, the cumulative rate
of enucleation was 12% (95% CI, 10%-15%). A detailed description of complications
and additional treatments during follow-up will be reported separately.
Complications following enucleation were similar to those already reported
for eyes with larger choroidal melanoma.32
Apart from ptosis and problems related to the implant and prosthesis, few
complications were reported during the first 5 years after enucleation.
DIAGNOSTIC ACCURACY
The Pathology Review Committee received sections for evaluation from
647 eyes of patients assigned to enucleation. The tumor in 2 (<1%) of the
647 eyes was judged to be adenocarcinoma, as reported previously.34 Among the remaining 645 eyes, tumors with both epithelioid
cells and spindle cells accounted for 551 (85%), epithelioid cells only for
19 (3%), and spindle cells only for 75 (12%). As already noted, 1 additional
eye assigned to enucleation was discovered after enrollment to have been misdiagnosed,
and the eye was not removed.
SURVIVAL OUTCOMES
The vital status of each patient had been updated during the 6-month
period prior to the analysis cutoff date for all but 54 patients—33
assigned to enucleation and 21 assigned to 125I brachytherapy.
One of these patients had been diagnosed with metastatic melanoma 2 years
earlier. (Shortly after the cutoff date for this analysis, 15 of the 21 brachytherapy
patients and 17 of the 33 enucleation patients were confirmed to be alive;
2 enucleation patients were reported to have died.) Only 5 patients had been
reported to be lost to follow-up by clinical center personnel.
As of the analysis date, 188 patients (28%) assigned to enucleation
and 176 patients (27%) assigned to 125I brachytherapy were known
to have died (P = .48). Cumulative mortality by time
since enrollment is displayed in Figure 1. The estimated 5-year cumulative mortality rates and 95% CIs were
19% (95% CI, 16%-23%) for patients in the enucleation arm and 18% (95% CI,
15%-21%) for patients in the brachytherapy arm. Adjustment for time since
enrollment using a Cox proportional hazards model with treatment arm as the
only covariate confirmed the nearly identical mortality rates in the 2 treatment
arms, with a risk ratio of 0.93 (95% CI, 0.76-1.14) for brachytherapy relative
to enucleation. This risk ratio and CI bounds are equivalent to a difference
in mortality rates of 1.3% in favor of brachytherapy bounded by 4.6% better
to 2.7% worse following brachytherapy than following enucleation.
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Figure 1. Cumulative proportion of patients
who died by time after enrollment. Numbers of patients at risk of death and
numbers censored are given at annual anniversaries of enrollment and randomization.
Ellipses indicate not applicable.
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Survival rates in the 2 treatment arms were examined within many subgroups
of patients defined on the basis of baseline demographic, medical, and tumor
characteristics: age, sex, ethnicity, educational attainment, smoking history,
history of cardiovascular disease and other conditions, apical height and
longest basal diameter of the choroidal melanoma, location and configuration
of the tumor, and time from diagnosis to enrollment in the clinical trial.
Among patients who reported graduation from high school without additional
years of education and patients without any coexisting disease at baseline,
unadjusted survival rates were somewhat better following brachytherapy than
following enucleation; among patients with coexisting cardiovascular disease
at baseline, unadjusted survival rates were somewhat better following enucleation
than following brachytherapy (P<.05 for all 3
univariate comparisons).
In a multivariate Cox proportional hazards survival model in which treatment
arm and baseline characteristics were included as covariates, age at time
of enrollment, apical height of the tumor, longest diameter of the tumor base,
distance from the proximal tumor border to the optic disc, tumor shape judged
from B-scan echograms, smoking status, and coexisting medical conditions had
independent and statistically significant effects on the length of survival
(P<.05). Adjustment for all baseline covariates
listed in the previous paragraph yielded an estimated risk ratio of 0.99 (95%
CI, 0.80-1.22). These risk ratios translate into a difference in mortality
of 0.2%, with this estimate bounded by 3.8% better to 4.2% worse following
brachytherapy than following enucleation. Thus, neither the adjusted nor unadjusted
mortality rates differed between the 2 treatment arms to a statistically or
clinically significant degree in this clinical trial. The 95% CIs for the
risk ratios suggest that the true relative difference in mortality, if any,
is less than 25%.
Of the 364 deaths from all causes, 345 (95%) had been reviewed and classified
by the Mortality Coding Committee. Findings from their reviews are summarized
in Table 10. Fewer than half
the decedents in each treatment arm were judged to have metastatic melanoma
at time of death; all but 1 of these 159 patients were judged by the Mortality
Coding Committee to have died because of the melanoma metastasis. The liver
was the most frequently reported site of metastasis, with multiple sites reported
for many patients. Metastatic melanoma was suspected to be present at death
in 43 additional patients based on clinical findings, but histopathologic
confirmation was not available. For 88 decedents (26%), there was no evidence
of malignancy at time of death.
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