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Assessment of Metastatic Disease Status at Death in 435 Patients With Large Choroidal Melanoma in the Collaborative Ocular Melanoma Study (COMS)
COMS Report No. 15
The Collaborative Ocular Melanoma Study Group
Arch Ophthalmol. 2001;119:670-676.
ABSTRACT
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Background A systematic review and assessment of disease-related mortality as part
of standardized prospective patient follow-up and evaluation within a multicenter
clinical trial have been lacking in previous studies of choroidal melanoma.
Objective To describe disease status at death in patients with large choroidal
melanoma treated and followed up in the Collaborative Ocular Melanoma Study
(COMS).
Design Analysis of reviews of patient status at death performed by the COMS
Mortality Coding Committee using available clinical and histopathologic information.
Setting and Patients Reviews of deaths as of July 31, 1997, the cutoff date for reporting
initial mortality findings.
Interventions Patients were treated by either enucleation preceded by external beam
radiotherapy or enucleation only.
Main Outcome Measures Disease status at the time of death and certainty associated with the
coding of disease status, sites of metastasis, and availability of autopsy.
Results Of 1003 patients enrolled in the trial, 457 had died; the estimated
median survival from time of enrollment was 7.4 years. Disease status at time
of death had been reviewed for 435 deaths (95%). The autopsy rate was 6%.
A total of 269 patients (62%) had histopathologically confirmed melanoma metastasis
at the time of death, and metastasis was suspected in 92 additional patients
(21%) on the basis of imaging and tests but without tissue confirmation. The
common sites were liver (93%), lung (24%), and bone (16%); multiple sites
were identified in 87% of patients with metastasis. The likelihood of 3 or
more sites increased more than 4-fold when autopsy results were available.
Conclusions Detailed mortality coding following a standard protocol provides the
most accurate reporting to date of disease-related mortality in patients with
choroidal melanoma and also identifies difficulties. Guidelines for the evaluation
of future patients in clinical studies of choroidal melanoma are suggested.
INTRODUCTION
METHODS FOR coding the disease status of a patient at the time of death
are important in clinical trials of interventions intended to prolong survival
or to prevent life-threatening complications. The effect of treatment on mortality
and, in particular, disease-related mortality is often the primary outcome
of interest. Assessment of disease-related mortality is essential in describing
the differential impact of various treatments on the subsequent history of
a disease and may lead to better strategies for evaluating and managing patients.
For patients with primary cancers, specification of the sites of metastatic
disease may provide useful information for the design of prophylactic or therapeutic
interventions.
Although rare, choroidal melanoma is the most common intraocular cancer
in adults,1 but little is known about the natural
history of choroidal melanoma and the patterns of mortality after treatment.
However, when metastasis occurs, the first site identified is usually the
liver, and the time between diagnosis of metastasis and death is often short.2 Previous studies3-16
of survival after treatment for choroidal melanoma have reported melanoma-specific
or tumor-related mortality rates. Various terms have been used to describe
deaths related to melanoma, including melanoma deaths, melanoma-related mortality, deaths from
malignant choroidal melanoma, and deaths from confirmed
metastatic uveal melanoma. In general, use of the term melanoma-related mortality has been based on varying sources of information:
contact with the patient, his or her family, or physicians who regularly followed
up the patient; death certificates; and/or other anecdotal information. Melanoma
metastasis is typically evaluated by tests or methods with varying sensitivity
and specificity: liver enzyme studies, liver scan, and/or biopsy or autopsy.10 In previous studies, both Seddon et al9
and Augsburger et al14 have categorized status
at death, based on information regarding the patient's most recent follow-up
contact, as dead of metastatic melanoma, dead of nonmelanoma cancer, or dead
of a noncancer cause. However, using this grouping, a death was assigned as
melanoma related even when the melanoma was not the patient's immediate or
underlying cause of death. Others also have coded melanoma-related mortality
on the basis of a history of metastatic melanoma11, 15
rather than on a review of clinical and histopathologic materials available
near the time of death.
As part of a meta-analysis of all-cause mortality following enucleation
for choroidal melanoma, we discovered that the arithmetic difference between
tumor-related and all-cause 5-year mortality rates in reports specifying both
ranged from 6% to 25%.17 Part of this variability
appeared to be due to differences in design, data collection, and patient
follow-up among these studies. Previous studies often have had retrospective
study designs in which patient information was retrieved after notification
of his or her death was received. Follow-up of patients in these studies may
not have been regular or complete, information leading to the diagnosis of
metastasis may not have been collected routinely, and the sites and extent
of metastasis may not have been documented. These problems can be minimized
in a prospective randomized controlled clinical trial for which standard schedules
and methods for patient follow-up and data collection provide mechanisms for
monitoring disease status over time and retrieving clinical information and
pathologic materials associated with a patient's death.
Methods for coding the metastatic status of patients at the time of
death were developed as part of the Collaborative Ocular Melanoma Study (COMS).
This article describes the methods and codings for patients in the COMS large
tumor trial; reports the results as of July 31, 1997, the cutoff date for
reporting the initial mortality findings; and discusses the implications of
these findings for this trial and others.
METHODS
The COMS is a set of multicenter randomized clinical trials designed
to evaluate the effectiveness of radiotherapy in comparison or in addition
to standard enucleation in prolonging survival of patients with choroidal
melanoma.18 The COMS trial for large choroidal
melanoma compared enucleation alone with enucleation preceded by external
beam radiation. Large tumors were defined as those for which ophthalmologists
agreed that the eye should be removed, ie, those greater than 10 mm in apical
height or at least 16 mm in diameter, or tumors 8 to 10 mm in apical height
but too close to the optic nerve for effective treatment with radiation without
irreversible damage to the optic nerve. In addition to requiring accurate
delineation by echography of the height of their unilateral primary choroidal
melanoma, patients were eligible for the trial only if they had no previous
diagnosis of metastasis or another primary cancer and also met the requirements
of a systemic evaluation, which included a chest x-ray examination and liver
function tests. Following enucleation, eyes were processed for histopathologic
confirmation of the diagnosis and cell type at the central COMS Pathology
Center (Madison, Wis).19 After treatment, patients
had an annual examination, which included ophthalmologic examinations of the
study eye and orbit and the fellow eye; a yearly physical examination; liver
function tests; and a chest x-ray examination for the detection of possible
melanoma metastasis. Whenever metastasis was suspected on the basis of these
evaluations or clinical judgment, the protocol recommended confirmation by
at least 1 diagnostic test, including computed tomographic scans, other imaging
scans, and/or biopsy or cytologic tests. When a diagnosis of melanoma metastasis
was made, a report of the diagnosis was submitted to the COMS Coordinating
Center (Baltimore, Md), along with reports of all procedures that were performed
to confirm the diagnosis. Biopsy or cytology slides or blocks of embedded
tissue were sent to the COMS Pathology Center for histopathologic review.
The COMS Mortality Coding Committee (MCC) was established to review
the clinical and pathologic information for deceased patients. This review
determined the status of tumor presence and site(s) of spread at the time
of a patient's death, documented the basis for such conclusions, and provided
the level of certainty regarding the determination. The MCC consisted of 6
members: a general anatomical pathologist, a medical oncologist, an ocular
pathologist, a biostatistician, an epidemiologist, and a coordinator from
the coordinating center. The MCC met twice annually to review records, which
included central histopathologic reviews and other clinical and histopathologic
information. Before MCC meetings, both MCC pathologists independently reviewed
each specimen sent to the COMS Pathology Center (central pathology) and assigned
it to 1 of the following categories on a form submitted to the COMS Coordinating
Center: diagnostic of metastatic malignant melanoma, consistent with metastatic
malignant melanoma, not consistent with metastatic malignant melanoma, no
tumor present, or tumor present but insufficient for diagnosis.
During MCC meetings, each patient's status at death was coded on a standard
form20 as follows: (1) dead with melanoma metastasis
(confirmed metastasis); (2) malignant tumor present, primary uncertain (suspected
metastasis); (3) malignant tumor present, not metastatic melanoma; (4) no
evidence of malignancy; or (5) inadequate evidence to establish presence of
malignancy. If status was coded as either of the first 2 categories, then
all metastatic sites and types of documentation also were recorded on the
form.
The level of certainty associated with the coding was based on the availability
of central or local pathology review of biopsy or autopsy materials. One of
3 categories was assigned to each death review: (1) confirmation of diagnosis
of metastatic melanoma from central pathology review of autopsy or biopsy
materials (high level of certainty), (2) tissue diagnosis of metastatic melanoma
made by a local pathologist (moderate level of certainty), or (3) no tissue
diagnosis available either locally or centrally (low level of certainty).
A case was coded as dead with melanoma metastasis or malignant tumor, primary
uncertain, only with histopathologic confirmation (either central or local).
A more detailed description of COMS mortality coding procedures has been given
elsewhere.21
The primary outcome of interest for this analysis was status at death
by the level of certainty associated with coding. Secondary outcomes of interest
were sites of metastasis, autopsy status, and availability of clinical and
histopathologic materials. SAS software (SAS Institute Inc, Cary, NC) was
used for all statistical analysis.
The COMS protocol and consent form were reviewed and approved by the
institutional review boards of all 43 participating clinical centers before
recruitment, and informed consent was obtained from all patients. Details
of the large tumor study design, methods, and baseline characteristics have
been reported elsewhere.18, 22-23
Patient accrual began on November 12, 1986, and ended on December 15, 1994;
initial mortality findings were published in 199823
and were based on follow-up as of July 31, 1997. This report focuses on patients
in the large tumor trial who had died and for whom mortality codings had been
performed by July 31, 1997.
RESULTS
A total of 1003 patients were enrolled in the COMS large tumor trial.
Patients were predominantly white (97%), 57% were male, and the mean age of
patients at the time of enrollment was approximately 60 years. Approximately
64% of patients were diagnosed as having metastasis within 6 years of enrollment;
the estimated median time from diagnosis of metastasis to death was slightly
greater than 6 months. A total of 457 patient deaths had been reported by
July 31, 1997,23 and the estimated median survival
from time of enrollment was 7.4 years. Of these 457 deaths, 435 patient files
(95%) had been reviewed by the MCC. Cases were coded as soon as available
information had been assembled, resulting in varying times to coding, ie,
within 6 months (146 [33%]), 6 to 12 months (164 [38%]), 12 to 24 months (69
[16%]), and more than 24 months (56 [13%]) after the patient's date of death.
Status at death by level of certainty is shown in Table 1. Slides were reviewed either both centrally and locally
(high level of certainty) (n = 259) or locally only (moderate level) (n =
39) in 298 cases; no tissue diagnosis (low level) was available for 137 cases
(31%). Overall, melanoma metastasis was confirmed (histopathologically confirmed
metastasis) in 269 cases (62%) and suspected (malignant tumor present but
uncertain primary tumor) in an additional 92 cases (21%), for a total of 361
cases. A malignant tumor other than choroidal melanoma was the cause of death
in 22 cases (5%). There was no evidence of metastasis or another cancer in
38 cases (9%) for whom sufficient clinical information was available; 14 cases
(3%) lacked adequate clinical information for definitive coding. Of 259 cases
with histopathologic or cytologic slides or specimens reviewed centrally,
93% were coded as dead with histologically confirmed melanoma metastasis;
in contrast, 74% of the 39 cases with local review only were coded as such
(data not shown). By definition, none of the 137 cases without tissue diagnosis
could be coded as dead with melanoma metastasis.
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Table 1. Status at Death by Level of Certainty Associated With Mortality
Coding
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The autopsy rate was less than 10% in most of the 43 clinical centers;
only 2 centers had autopsy rates exceeding 20%: 25% and 50% in centers reporting
12 and 4 deaths, respectively. Sixteen centers had autopsy information for
at least 1 death. University centers had higher autopsy rates than other types
of centers. Overall, autopsy results were available for only 28 (6%) of the
435 patients: 26 (7%) of the 361 patients with either histopathologically
confirmed or suspected metastasis and 2 (3%) of the 74 patients without metastasis. Table 2 depicts the distribution of these
361 cases by autopsy status and the substantially larger proportion of histopathologically
confirmed deaths with melanoma metastasis of patients with autopsies.
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Table 2. Status at Death by Autopsy Status for Patients With Confirmed
or Suspected Metastasis
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Table 3 shows the distribution
of coded sites of metastasis, based on available information, by autopsy status
of patients. The most common sites were liver (93%), lung (24%), bone (16%),
skin or subcutaneous tissue (11%), and lymph nodes (10%). In cases with autopsies,
liver (100%) and lung (50%) involvement exceeded that in cases without autopsies
(93% and 22%, respectively). Multiple sites of metastasis were prevalent (Table 4). For the 361 patients with confirmed
or suspected metastasis, 204 (57%) had evidence of metastasis in a single
site, 73 (20%) in 2 sites, 47 (13%) in 3 sites, and 37 (10%) in 4 or more
sites. Of the 204 cases with only 1 site of metastasis, the liver was involved
in 193 patients (95%) (data not shown). Of the 336 patients with liver as
a site of recurrence, only 193 (57%) had liver as the only site (Table 5).
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Table 3. Sites of Metastasis at Time of Death by Autopsy Status for
Patients With Confirmed or Suspected Metastasis
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Table 4. Number of Sites of Metastasis at Time of Death by Autopsy
Status for Patients With Confirmed or Suspected Metastasis
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Table 5. Sites of Metastasis for Patients With Liver as a Site of Confirmed
or Suspected Metastasis
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Many types of records were reviewed by the MCC to make their assessments
(Table 6). Official certification
of death was available for nearly all patients. A physical examination report
or clinical summary, liver function results, and computed tomographic scan
reports close to the time of death were available in 74%, 68%, and 62% of
the cases, respectively. X-ray reports and liver biopsy reports were available
less often, ie, in 38% and 32% of the cases, respectively. Multiple biopsy
or scan reports were often available for the same patient. As expected, greater
availability of clinical and pathologic materials for review resulted in more
definitive codings of status at death and sites of metastasis. The availability
of materials for review and the distribution of codings did not differ substantially
by treatment arm.
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Table 6. Materials Reviewed by the Mortality Coding Committee
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Initial mortality comparisons indicated no statistically significant
difference in overall survival by treatment.23
The Kaplan-Meier estimate of 5-year all-cause mortality was 40%.23
On the basis of the histopathologically confirmed deaths from metastatic melanoma,
the estimate of 5-year melanoma-related mortality was 27%,23
an arithmetic difference of 13% between tumor-related and all-cause mortality
rates in this clinical trial. A less rigid definition of death with melanoma
metastasis, ie, inclusion of malignant tumors with uncertain primary origin,
would decrease this difference further to 5%.
COMMENT
The COMS large tumor trial has provided the largest reported series
of patients with metastatic ocular melanoma and the only series resulting
from a randomized controlled clinical trial with standardized follow-up and
systematic data collection and mortality coding. The assessment of disease-related
mortality for any condition depends on available clinical and histopathologic
information and the criteria established by the coders. In the COMS clinical
trial for large choroidal melanoma, regularly scheduled follow-up examination
and systematic collection and review of all records pertinent to death and
events preceding death permitted us to categorize accurately patient status
at time of death with respect to metastasis after a diagnosis of choroidal
melanoma. The mortality findings of our study have high external validity
and should be applicable to all patients with large choroidal melanoma who
satisfy the COMS eligibility criteria.22 In
our study, 62% of deaths were associated with histopathologically confirmed
metastasis; metastasis was suspected in the absence of tissue confirmation
in an additional 21%. Overall, 43% of patients with confirmed or suspected
metastasis had more than a single site of involvement; 20%, 13%, and 10% had
2, 3, or 4 or more sites of involvement, respectively. One unusual case of
solitary cardiac metastasis was observed.24
We observed, however, when autopsy information was available, that 77% of
patients had more than 1 site of metastasis; 39% had 4 or more sites. Although
our autopsy rate of 6% is low, it is comparable to current estimates.25
Other investigators have described patterns of metastatic spread in
smaller series of patients with choroidal melanoma (Table 7). Although, as observed in our study, the liver is the most
frequent site of metastasis, the sites and extent of dissemination vary across
case series, reflecting differences in patient populations, study designs,
diagnostic procedures, and data collection over time and across studies. In
other series, the proportion of cases with liver metastasis ranged from 56%
in cases diagnosed by biopsy or clinical criteria to 100% in autopsy cases
(Table 7). In our series, the
liver was a site of metastasis in 93% of total deaths with metastasis and
in 100% of the 26 cases with available autopsy information. Although an annual
chest x-ray examination was required in the COMS, the relative frequency of
diagnosis of lung metastasis was 24% (50% in autopsy cases); this proportion
varied from 20% to 55% in the other series. Our findings are similar to those
of the series by Rajpal et al30 of 35 cases
(33 with autopsy); the variation may be due to differences in the patient
populations. The series by Rajpal et al and other series consisted of small
numbers of patients who were referred for treatment of metastatic disease
and were not necessarily representative of all patients with metastasis. Of
patients with confirmed or suspected metastasis at time of death in our series,
fewer than 40% were reported by the clinical centers to have received treatment
for metastatic disease at the time of diagnosis (data not shown). As of our
cutoff date for this analysis, most of such patients had received chemotherapy.
We will investigate the association between treatment and patterns of metastasis
as our trial progresses.
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Table 7. Reported Patterns of Metastasis From Choroidal Melanoma
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The progression of choroidal melanoma and its propensity to metastasize
to the liver, confirmed in this study, differ from progression and metastatic
spread of cutaneous melanoma, which is primarily to the lymph nodes and lung.2, 34-35 Our findings suggest
guidelines for evaluation of future patients with ocular melanoma. The COMS
protocol specifies annual follow-up, including a routine medical examination,
liver function studies, and chest x-ray examination. Any suggestion of metastasis
based on these evaluations is followed by diagnostic procedures, including
computed tomographic scan or other imaging procedures and, if indicated, a
biopsy.36 These steps follow the recommendations
of Pach and Robertson.37 A recent assessment
by Eskelin et al38 supports this approach at
baseline and follow-up. However, Hicks et al39
concluded that all single liver function tests had poor sensitivity for metastatic
disease and recommended routine liver ultrasonography at both presentation
and follow-up. New genetic, histopathologic,40-41
metabolic, and molecular biologic predictors of metastasis may be more useful
prognostic indicators than screening or imaging tests.
Once metastatic ocular melanoma is detected, no effective method of
systemic treatment has been identified,42-44
although one small series of patients with curative resection of metastasis
exhibited improved survival.45 Treatment of
only the liver by surgical resection or chemoembolization probably has not
been effective because, as demonstrated in our patients, tumor dissemination
elsewhere is also likely. The high rate of metastasis of choroidal melanoma,
despite treatment of the primary tumor, and the short time from the clinical
diagnosis of metastasis to death from metastatic melanoma32
suggest that adjuvant systemic treatment at the time of initial treatment
of the choroidal melanoma may prove a more effective approach to reducing
death due to melanoma metastasis. Identification of promising adjuvant therapies
for metastatic melanoma of the choroid and evaluation in randomized controlled
clinical trials are needed.
AUTHOR INFORMATION
Accepted for publication December 15, 2000.
The COMS has received support from the National Eye Institute and the
National Cancer Institute through cooperative agreements EY06253, EY06257,
EY06258, EY06259, EY6260, EY06264, EY06265, EY06266, EY06268, EY06269, EY06270,
EY06274, EY06275, EY06276, EY06279, EY06280, EY06282, EY06283, EY06284, EY06287,
EY06288, EY06289, EY06291, EY06839, EY06843, EY06844, EY06848, EY06858, and
EY06899 with the National Institutes of Health, Bethesda, Md.
Nancy Robinson, BA, and Michele Zimbric, BS, coordinated central review
of autopsy, biopsy, and cytology materials by the MCC pathologists.
Corresponding author: Marie Diener-West, PhD, COMS Coordinating Center,
Wilmer Clinical Trials and Biometry, 550 N Broadway, Ninth Floor, Baltimore,
MD 21205 (e-mail: mdiener{at}jhmi.edu).
Reprints:
COMS Coordinating Center, Wilmer Clinical Trials and Biometry, 550 N Broadway,
Ninth Floor, Baltimore, MD 21205.
Prepared by the COMS Mortality Coding Committee: James K.V. Willson,
MD, Daniel M. Albert, MD, Marie Diener-West, PhD, Lee McCaffrey, MA, Claudia
S. Moy, PhD, and Robert E. Scully, MD. A complete listing of the COMS Group
was published previously (Control Clin Trials.
1993;14:352-391; Am J Ophthalmol. 1998;125:745-766).
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