COMS - INTERNET

Purpose of the COMS

The Collaborative Ocular Melanoma Study (COMS) is a multicenter investigation designed to evaluate
therapeutic interventions for patients who have choroidal melanoma. Evaluations conducted in the COMS are
aimed at determining which of two alternative therapies better prolongs the remaining lifetime of individuals
diagnosed as having choroidal melanoma and, if two alternatives provide similar expectations of survival, to
determine which offers the patient the longer cancer-free life and the better prognosis for vision overall.
Currently, two randomized controlled trials are being conducted as separate substudies:
 Comparison of enucleation versus radiation for tumors at least 2.5 mm but no more than 10 mm in
height and no more than 16 mm in basal diameter;
 Comparison of standard enucleation versus enucleation preceded by external beam radiation for tumors
greater than 10 mm in height or greater than 2 mm in height and greater than 16 mm in basal diameter or
greater than 8 mm in height if there is optic nerve involvement.
In addition to the two randomized trials, a number of pilot studies and ancillary studies have been and continue
to be conducted by COMS investigators.

Chronology of Significant Events

Septe
mber Funding awarded by the National Eye Institute
1985
Nove
mber First patient randomized in large tumor trial
1986
Januar
y First patient randomized in medium tumor trial
1987
Dece
mber Patient enrollment of large tumor trial completed
1994
June
Initial survival data from large tumor trial published
1998
July
Patient enrollment in medium tumor trial completed
1998

Design of the COMS

The design of the COMS is characterized by:
 Multicenter organization
 Standard protocol followed in all centers for initial evaluation, patient entry and randomization,
treatment, and follow-up
 Standard data collection forms designed specifically for the COMS
 Standard eligibility and exclusion criteria
 Scheduled follow-up of all patients at comparable intervals
 Random allocation of management strategy
 Central allocation of random assignment
 Informed consent according to COMS guidelines
 Certification of clinic personnel and clinical centers
 Central monitoring of radiation treatment
 Concurrent data processing
  Ongoing quality assurance and monitoring program for all aspects of Study operations
 Central data processing and analysis
 Central confirmation of the diagnosis from photoechograms, color photographs, and fluorescein
angiograms
 Central histopathologic diagnosis for all patients whose eyes are enucleated
 Periodic reports on performance of all centers
 Periodic analysis of accumulating data for review by the Data and Safety Monitoring Committee
Patient Enrollment and Informed Consent

Adherence to the enrollment criteria is monitored at the Coordinating Center, the Echography Center, and
the Photograph Reading Center.

Considerable attention is given to education of the patient and family members in order to assure that they
understand the nature of the malignancy, the treatment options available, and the rationale for asking the
patient to participate in a randomized trial. The patient education and orientation activities are important
parts of the complete informed consent process and are described in detail in The COMS Manual of
Procedures.

All patients enrolled in the COMS have a right to be informed regarding:

 The purpose of the study

 The fact that the management strategy is chosen at random from the two believed to be the best
candidates on the basis of size of the tumor in the patient's eye

 The commitment to long-term follow-up that is being made by the patient

 The commitment to long-term care and attention being made by the COMS clinical center
physicians and staff

In addition, the patient has a right to know how much the evaluation and treatment procedures cost, as in any
health care setting, and that neither the patient nor the health insurer is expected to pay for research costs.

Patient Follow-up

A standard follow-up schedule is used for all patients enrolled in each substudy. The follow-up schedule and
an overview of patient visits for evaluation and data collection purposes are given in The COMS Manual of
Procedures. Patients enrolled in the randomized trials are followed for at least ten years after enrollment or
to death.

Sample Size

The COMS investigators estimate that the randomized trial comparing enucleation with I-125 plaque
radiation for medium melanomas will require about 2400 patients to be able to detect a 25% relative
difference in cumulative five-year mortality with reasonable confidence. The sample size is subject to
periodic review by the Data and Safety Monitoring Committee in order to check the accuracy of the
assumptions on which it has been based and to make refinements as necessary. Enrollement in the trial for
medium-sized melanoma is ongoing.

For the randomized trial comparing standard enucleation with enucleation preceded by external beam
radiation for large melanomas, the investigators estimated that approximately 1000 patients were required.
Accrual to the trial for large sized melanoma was closed in December 1995, with 1,003 patients enrolled.

Study Outcomes
  The primary comparison of interest in each randomized trial is the difference between the two
management groups with respect to all-cause mortality after entry into the COMS.

 Cancer-free and metastasis-free survival are based on the judgements of the Mortality Coding
Committee regarding whether metastatic disease or other cancer was present at the time of death and is
based on reports from the clinical centers of diagnosis of metastasis and other malignancies as well as on
histopathologic review of tumor biopsies taken at the time of diagnosis of the matastasis or at autopsy.

 Years of useful vision is of interest for all patients, whether or not the Study eye is retained; visual
acuity is assessed during each clinic visit for both the fellow eye and the Study eye, if present. For
patients in the trial for medium tumors, visual status of the plaqued eye is followed in order to determine
the impact of I-125 radiotherapy on visual ability. Vision of the fellow eye for patients in both trials is
also measured in order to assess the risk of vision loss due to radiation to the Study eye.
The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation
radiation of large choroidal melanoma III: local complications and observations following
enucleation COMS report no. 11

PURPOSE

To summarize local complications and observations following enucleation of eyes with large choroidal
melanoma that were reported prospectively at scheduled examinations of patients enrolled in the
Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation.

METHODS

Of 1,003 patients with large choroidal melanoma who were assigned randomly at time of enrollment to
enucleation alone or to pre-enucleation radiation, 994 were treated as assigned. Complications and
observations were reported to the Coordinating Center on standard forms completed at the time of
enucleation surgery and during the immediate 24-hour postsurgery period, 1 to 6 weeks following
surgery, 6 and 12 months after enucleation, and at examinations scheduled at 12-month intervals
thereafter.

RESULTS

The most common perioperative complication was pain that prolonged hospital stay, which was reported
for six patients (1%) who had standard enucleation and eight patients (2%) who had pre-enucleation
radiation. Patients treated with pre-enucleation radiation had somewhat more complications reported at
the examination 1 to 6 weeks after surgery than did patients treated with enucleation alone, 36 (8%) and
21 (4%), respectively (P = .03, 2 test), but all complications were minor. During follow-up, fewer
biopsy-confirmed tumor recurrences in the orbit were observed among patients treated with pre-
enucleation radiation than with enucleation alone (0 vs 5, respectively; P = .03, Fisher exact test).
Patients treated with pre-enucleation radiation also had a lower incidence of severe ptosis than did
patients treated with enucleation alone (P = .007, log rank test). Among 307 patients examined 5 years
after enucleation, the most frequent complication reported at the 5-year examination was poor prosthetic
motility for 24 patients (16%) treated with enucleation alone and 30 patients (19%) treated with pre-
enucleation radiation.

CONCLUSIONS

Complications were infrequent during the 5-year period following enucleation surgery. Five-year
incidence rates and prevalence at the 5-year examination of most complications were similar in the two
treatment arms. There was no indication that pre-enucleation radiation had resulted in more serious
complications.
The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation
radiation of large choroidal melanoma II: initial mortality findings COMS report no. 10

Purpose: To report initial mortality findings from the Collaborative Ocular Melanoma Study (COMS)
randomized clinical trial of pre-enucleation radiation of large choroidal melanoma.

Methods: Patients were evaluated for eligibility at one of 43 participating centers in the United States
and Canada. Eligible consenting patients were assigned randomly at the time of enrollment to standard
enucleation or to external radiation of the orbit and globe prior to enucleation. Eligibility was confirmed
at the COMS Coordinating Center, Echography Center, and Photograph Reading Center. Adherence to
the radiotherapy protocol was monitored at the Radiological Physics Center. The diagnosis of choroidal
melanoma was confirmed following enucleation by a three-member Pathology Review Committee.
Patient accrual began in November 1986 and was completed in December 1994; 1,003 patients enrolled.
Patients have been followed at annual clinical examinations. Cause of death was coded by a Mortality
Coding Committee whose members were not involved in the care of COMS patients; the clinical trial
was monitored by an independent Data and Safety Monitoring Committee.

Results: A total of 1,003 patients were enrolled; 506 were assigned to enucleation alone and 497 to pre-
enucleation radiation. Treatment groups were well balanced on baseline characteristics. Only nine
patients were found to be ineligible after enrollment, seven in the interval between randomization and
enucleation and two after enucleation based on histopathology. All but nine patients were treated as
assigned; in only six of 491 eyes treated with pre-enucleation radiation was there a major deviation from
the radiotherapy protocol. With 5-year outcome known for 801 patients enrolled (80%), the estimated 5-
year survival rates and 95% confidence intervals (CIs) were 57% (95% CI, 52% to 62%) for enucleation
alone and 62% (95% CI, 57% to 66%) for pre-enucleation radiation. Among the baseline covariates
evaluated, only age and longest basal diameter of the melanoma affected the prognosis for survival to a
statistically significant degree. The risk of death among patients treated with pre-enucleation radiation
relative to those treated with enucleation alone after adjustment for baseline characteristics of patients,
eyes, and tumors was 1.03 (95% CI, 0.85 to 1.25). Of 435 deaths classified by the Mortality Coding
Committee, 269 patients had histologically confirmed melanoma metastases at the time of death.
Estimated 5-year survival rates for this secondary outcome were 72% (95% CI, 68% to 76%) for
enucleation alone and 74% (95% CI, 69% to 78%) for pre-enucleation radiation.

Conclusions: No survival difference attributable to pre-enucleation radiation of large choroidal

melanoma, using the COMS fractionation schedule, has been demonstrated to date in this randomized
trial. The trial had statistical power of 90% to detect a relative difference in mortality rates between the
two treatment arms of 20% or larger. A smaller difference is possible, but a clinically meaningful
difference in mortality rates, whether from all causes or from metastatic melanoma, is unlikely.

The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation

radiation of large choroidal melanoma I: characteristics of patients enrolled and not enrolled
COMS report no. 9

Purpose: To describe the baseline characteristics and status of patients enrolled in the Collaborative
Ocular Melanoma Study (COMS) randomized clinical trial of pre-enucleation radiation of large
choroidal melanoma conducted in the United States and Canada, and to compare characteristics of
patients enrolled with those of patients with tumors of eligible size who were not enrolled in order to
assess the generalizability of findings from the clinical trial.

Methods: For all patients evaluated for the clinical trial at COMS centers from November 1986 through
December 15, 1994, selected data were transmitted to the COMS Coordinating Center. For patients who
enrolled in the clinical trial, ophthalmic and medical history, examination findings, and visual acuity
 measurements were recorded prior to enrollment. Standardized A-scan and contact B-scan echographic
examinations were performed prior to enrollment, and photoechograms were submitted for central
review for consistency with the diagnosis, independent measurement of the apical height of the tumor,
and description of tumor configuration and internal reflectivity for each patient enrolled. Until January
1992, wide-angle fundus photographs and fluorescein angiograms taken prior to enrollment also were
submitted for central review to confirm consistency with the diagnosis. All data were integrated and
analyzed at the COMS Coordinating Center.

Results: Of 6,078 patients with choroidal melanoma evaluated in COMS centers, 1,860 had tumors of
eligible size; of these, 1,302 (70%) were eligible for the clinical trial, and 1,003 (77% of eligible
patients) enrolled. The two principal reasons for ineligibility were other primary cancer and
predominantly ciliary body melanoma. Ineligible patients were older than eligible patients, had larger
choroidal melanoma, and had poorer visual acuity at the time of evaluation for the COMS (P < .01,
Wilcoxon rank sum tests). Patients eligible for the clinical trial had a mean age of 60 years; 56% were
male; almost all (97%) were non-Hispanic whites. Among eligible patients, mean tumor apical height
was 9.5 mm and mean longest basal diameter was 17.2 mm. Eligible patients who enrolled in the trial
were similar to eligible patients who did not enroll with respect to most factors considered. Those who
enrolled had longer tumor basal diameter and better visual acuity in the fellow eye, more often had their
primary residence in Canada, and less often had education beyond high school than did eligible patients
who did not enroll (P < .05, Wilcoxon rank sum tests and 2 tests, respectively).

Conclusions: The COMS clinical trial of pre-enucleation radiation was designed to yield internally valid
treatment comparisons through random treatment assignment at time of enrollment. Findings also have
high external validity because a majority (54%) of all patients with tumors of eligible size, and a large
majority (77%) of all eligible patients, were enrolled. Furthermore, patient characteristics are similar to
those of patients included in other evaluations of this method of treating large choroidal melanoma.
Thus, findings from this clinical trial apply to all patients who have large choroidal melanoma and
satisfy COMS eligibility criteria.
Uveal melanoma: updated considerations on current management modalities
Willem A. Manschot1, William R. Lee2 & Roel van Strik3
1
Institute of Pathology; 3 Institute of Epidemiology and Biostatistics, Erasmus University, Rotterdam, The
Netherlands; 2 Departments of Ophthalmology and Pathology, University of Glasgow, Glasgow, Scotland
Accepted 30 November1995
Abstract
Published data on growth rates of uveal melanomas and effects of treatment modalities raise important
considerations. Dissemination from uveal melanomas starts after the tumour is larger than 7 mm diameter;
growth from 7 to 10 mm diameter increases the risk of metastases incrementally to approximately 16%
Estimations of tumour doubling times indicate that metastatic death before 8 years is nearly always due to pre-
therapeutic dissemination so that the impact on survival by therapy can only be assessed thereafter.
Histopathology on irradiated melanomas reveals that reproductive activity has not been suppressed and the
anticipated (and unfavourable) risk of metastases is not balanced by poor postirradiation visual acuity. Also the
psychological wellbeing of a patient with a functional fellow eye is better after primary enucleation.
Conservative management is most appropriate for: small melanomas, patients with a short life expectancy,
melanomas in a single functioning eye, and patients refusing enucleation.
Optimum treatment of any form of neoplastic disease by modern therapeutic modalities should ideally be based
on an accurate knowledge of the biological behaviour of the specific neoplastic process. With regard to ocular
melanomas, there are serious gaps in knowledge concerning growth rates in situ and in the documentation of the
time intervals between the presentation of the primary tumour and the appearance of metastases. The rarity of the
tumour necessitates careful accumulation of data, so that an adequate analysis can be made of the claimed
success of cure rates. Equally important, the side effects and the complications of treatment should be the subject
of careful scrutiny. In this communication the literature on the relevant aspects of melanoma biology and current
treatment modalities is critically analysed.
Tumour biology
Tumour doubling time
Information on tumour doubling time of uveal melanomas was introduced in 1980 [1] and updated reviews were
provided in 1987 [2] and in 1992 [3]. From this data it was possible to estimate the risk of metastatic disease in
relation to the dimensions of the tumour. The application of meta analysis provided by Diener-West and
associates [4] and Markowitz et al. [5] has indicated that a radical reappraisal of the current philosophy of
management is required.
When do uveal melanomas metastasize?
Table 1. Metastatic death after enucleation small melanomas. Davidorf et al. [8].

Diameter < 10 mm < 7 mm 7-10 mm

Number cases 50 18 32
Number 10 yr follow-up 18 + 3 tumour death ? ?
Lost to follow-up 29 ? ?
Tumour-related death 5 (10%) 0 5 (16%)

Table 2. Metastatic death after enucleation small melanomas. Thomas et al. [9].

Diameter < 10 mm < 7 mm 7-10 mm

Number cases 65 42 23
Number 10 yr follow-up 27 (0 tumour death) ? ?
Lost to follow-up 38 ? ?
Tumour-related death 6 (9%) 0 6 (26%)
In 1984, an editorial in the American Journal of Ophthalmology stated that 'it is unclear at what stage in its
course a uveal melanoma develops the capacity to metastasize' [6]. However an analysis of the data then
available in the literature provided evidence which indicated that metastatic disease does not occur until the
tumour dimensions are greater than a diameter of 6-7 mm [7]. This conclusion was based on two separate studies
of survival from small melanomas treated by enucleation [8, 9]. In both series [8, 9], metastatic death had not
occurred in the <7 mm diameter groups, but had occurred in 10% [8] and 9% [9] in the < 10 mm diameter
groups; it is noteworthy that the < 10 mm group also included the <7 mm cases. Recalculation of this data [8, 9]
revealed that the percentage metastatic death rate in the group tumours measuring 7-10 mm in diameter groups
appeared to be 16% and 26%, against zero in the <7 mm diameter groups (Tables 1,2). There are exceptions,
however: one patient with a melanoma <7 mm had metastases, but had not yet died. In the literature thereafter,
only one more case of metastatic death after enucleation in a patient with a < 7 mm melanoma has been reported
[10]. This data strongly suggests that choroidal melanomas rarely metastasize when the tumours have a diameter
less than 6-7 mm at the time of detection.
Death rates in patients with melanomas less than 10 mm diameter
The previously cited editorial [6] also stated that patients with melanomas < 10 mm diameter had 'an excellent
prognosis regardless of treatment; the five-year tumour-related mortality in this group is less than 5%' This
statement, clearly contradicted by the observation shown in Tables 1 and 2, can be seriously challenged by the
application of meta-analysis, which provides proof that five-year mortality rate in patients with melanomas < 10
mm diameter is 16% [4]. This implies that prolonged clinical observation of melanomas as they enlarge from 7
mm diameter to 10 mm diameter could result in the death of 16% of these patients. However it is too simplistic
to suggest that all such patients with small pigmented tumours of 6-7 mm or less should be treated by immediate
enucleation since many such tumours could be nævi and the majority of melanomas are not brought to the
attention of ophthalmologists at this stage. Nonetheless on theoretical grounds, metastatic death could have been
averted by complete eradication of the malignant neoplasm at the 6-7 mm stage and this important postulate
should not be neglected.
Failure to appreciate the consequences of 'doubling time'
The new approach to uveal melanomas, published in 1980 [1], with regard to their biological behaviour, was
based on the published data on skin melanomas, for which tumour doubling times (Td's) had been calculated.
Information derived from this literature showed that the time intervals between dissemination and metastatic
death were widely spread and varied between 3 and 30 years.
Subsequently numerous reports on tumour doubling times in uveal melanomas have been provided [11-14]; in
only three out of thirtynine patients were the doubling times estimated to be shorter than 69 days.
On theoretical grounds it has been suggested that metastatic tumour death (after the primary tumour has released
cells into the circulation) will occur at a time interval derived from multiplication of the tumour doubling time
by 35-40 [15]. This postulate (which does not assume that all metastases grow exponentially from the first cell
division to a clinically detectable size, because the tumour doubling time represents a mean value) has not been
contradicted in later studies [see reference 3], which have repeated and extended the fundamental work of
Collins [15].
Taking these two assumptions together, it may, therefore, be accepted for practical therapeutic and prognostic
considerations in individual patients, that death from metastatic death in unlikely to occur before 35 x 69 days or
no less than six years after dissemination of the first viable embolus of tumour cells.
Furthermore, since the tumour doubling times of uveal melanomas may exceed 299 days, the time interval
between dissemination and metastatic death may vary widely and range from 6 to 60 years. Crowley [16]
reported a mean disease-free interval for cutaneous melanomas of 14.3 years and compared this with 22.3 years
for primary ocular lesions. It is noteworthy that in this series [16], five out of twelve ocular melanoma patients
had a tumour-free interval of 47, 45, 30, 28 and 27 years, respectively.
The minimal latent interval of six years implies that metastatic death within 7-8 years after local therapy on the
uveal melanoma is nearly always due to pretherapeutic dissemination. This is the only reason why a statistically
significant impact on survival has never been and never will be established by a detailed analytical comparison
of survival rates within 8-10 years after various conservative interventions, after primary enucleation or after
observation only. It is therefore more likely that differences in survival rates after any given form of treatment
will reflect the selection criteria for patients subjected to that specific form of treatment. The validity of this
postulate is supported by the agreement in all reports, that within the first 8-10 years no significant difference in
survival rate has ever been noted when various treatment modalities are compared [17-21] or when survival in
'promptly treated patients' is compared with those in whom 'treatment has been delayed' [22].
Therefore, the essential requirements for valid statistical comparisons are:
- a 10-15 year survival rate of all treated patients, and
- accurate assessment of visual function in all living patients after a 5-year or more follow-up, without any
selection bias.
Many ophthalmic oncology institutes have employed conservative management in uveal melanomas for 15-20
years, but rather surprisingly, results after follow-up periods of 10 years or more of all treated patients have not
been made available. Neglect in providing this fundamental information has been highlighted by Markowitz et
al. [5], who emphasized that researchers, clinicians, journal editors, and reviewers should be more attentive to
the completeness of reports from clinical research studies; attention to basic information regarding design and
methods was strongly recommended. Statements made by these authors [5] concerning the overall quality of
reporting (which have not improved over the last two decades) should not be ignored. Publication of unverifiable
data still continues e.g. visual acuities between 6/24 and zero are unspecified, and statements such as 'stable
disease' defined as 'an elevated remnant, remaining unchanged for at least one year' are equally vague [23].
Tumour biology in relation to ionising radiation.
A consideration of the histopathological findings in 231 eyes containing irradiated melanomas was provided in
1992 [3]. Thereafter, another 170 such pathological studies have been reported [24-31]. A substantial number of
irradiated tumours are treated successfully, but the actual percentage of loss of proliferative capacity of all stem
cells will never be known. To compound the difficulty in assessment, a sufficient follow-up period for all
irradiated patients may never be achieved and by the very nature of the treatment, radiotherapy is applied to
'masses' which are not histologically classified.
The well-established radio-insensitivity of uveal melanomas is reflected in the absence of radiation-induced
necrosis in about 40% of the treated tumours, and in the identification of well preserved tumour cells in about
95% of the specimens [3]. Appearances suggesting continuing tumour cell activity was noted in ruthenium106-
irradiated melanomas in 55 of 56 cases [24]. On the other hand, microscopically complete tumour necrosis was
found in 10 out of 25 large melanomas, measuring > 7-8 mm in height after iodine1 25-brachytherapy [25]. In
another report unequivocal mitoses were found in 36% of tumours, treated with various types of radioactive
plaques: enucleation was performed at an average of 29 months after therapy [26]. Mitoses were also reported in
20% of 25 ruthenium1 06-treated melanomas [27]. Mitoses after proton beam irradiation have been described in
9 (27%) of 33 melanomas [28]. Similar data was obtained from five proton beam-treated tumours in five patients
[29] and in four of seven cases [30]. The two latter reports noted intervals between irradiation and enucleation of
36, 49 and 66 months. Mitoses in a growing tumour and mitoses of more than two years after irradiation must be
regarded as significant indicators of the presence of viable tumour stem cells. Their presence indicates a failure
of irradiation to abolish the proliferative capacity of the stem cells within the tumour.
Clinical implications
The importance of long-term visual acuity data
Preservation of vision is the principle justification for conservative management of ocular melanomas. It is
unfortunate therefore, that some of the radiotherapeutic and surgical centres which publish regularly, have been
reluctant to present verifiable, detailed data on the retained visual acuity of all treated patients. In general,
follow-up periods of visual function have been shorter than those for other data relevant to the treatment and
further management of the patients. An extreme example of a great potential for bias is presented in a report [32]
published in 1993, on 163 patients who had been treated between 1972 and 1991. This study mentions only a
'one-year (!) post-operatively retained visual acuity of all patients'. Moreover, vision had been measured with a
pinhole aperture. The reported visual acuity is, therefore, in no sense representative of the post-therapeutic
quality of life of these patients.
An appropriate method of analysing the published accounts of post-therapeutic visual function would be to
arrange the data according to various irradiation modalitis (Table 3).
The lack of uniformity in the published information prevented the use of one scale in this table, so that proper
comparisons could not be made and the data not added. It would be highly desirable if the Collaborative Ocular
Melanoma Study (COMS) and those large centres, which do not participate in the COMS, could reach an
agreement to use identical designs and methods for their future follow-up reports. This would enable an
appropriate long-term appraisal of the data for retention of useful visual function, particularly with reference to
different treatment modalities.
It may be noted that some numbers and percentages in Table 3 do not correspond with the data provided in the
original reports. Several authors used percentages which did not refer to all treated patients, but to selected sub-
groups. As far as possible, the recalculated data in Table 3 refer to all treated patients. The information provided
confirms that visual acuity has decreased to <6/60 in about 50% of the eyes, three years after irradiation using
any modality. A continuing decrease in visual acuity of about 10% per annum has also been noted [40]. A
randomized study [36] to compare the results of helium ion irradiation versus 1125-brachytherapy showed that
visual acuity had decreased by >= 4 lines in 69% of each group. Another study on visual acuity after 1125-
therapy [37] revealed that 49 (78%) of 63 patients had an acuity decreased to <= 6/30, or an acuity which had
decreased 2 lines or more. It was concluded that the eye encounters significant morbidity after 1125-irradiation.
Data on post-therapeutic visual acuity after ruthenium106, cobalt60 and proton beam irradiation have either not
been published, or have been reported in an incomplete fashion, with short follow-up periods, which prevent
comparison with other therapeutic modalities.
After five years, some 70% or more of irradiated eyes in which data were verifiable had retained a visual acuity
of <= 6/60 (Table 3). A case report [41] mentions a maintained reading vision 10 years after proton beam
irradiation of a histologically proven macular melanoma. The generally poor visual result however questions the
authenticity of the 'fight for sight' justification for conservative treatment. The anticipated incremental ratio of
the 'unfavourable risk' of post-therapeutic dissemination from retained viable tumour stem cells against the
'benefit' of the conservative procedure cannot be assessed before ten post-therapeutic years, due to our inability
to control metastatic disease.
The future quality of life after treatment
There is little consideration in the literature on conservative management of the post-therapeutic physical and
psychological stresses imposed on the treated patients. Considerable anxiety arises from frequent re-
examination, re-treatment of recurrence, and the treatment of the complications after irradiation [29, 30, 37, 42,
43] or intraocular surgery [32]. This contrasts with patients treated by primary enucleation, who, moreover, are
unaware of the anxious and depressing burden of harbouring an intraocular malignancy, which might continually
have the capacity to disseminate and to cause a much feared metastatic death.
By contrast, the impact of enucleation on the post-surgical quality of life has not been found to be significant in
four vision-dependent activities: viz. working; driving, reading and television viewing in 62 (87%) of 71 patients
[44]. Fifteen years after enucleation, 18/20 (90%) of patients retained the ability to drive and 25/26 (96%)
retained the ability to read. Another comparative study on the same four post-enucleation vision-dependent
activities as against those of brachytherapy [45] revealed that 48/51 (94%) of the patients after enucleation and
46/51 (90%) of those after irradiation - mean follow-up of respectively 89 and 87 months - reported no vision-
related change in any of these four activities. It appears questionable, therefore, to burden a patient with a
normally functioning fellow-eye with the incremental risk of preventable metastatic death by post-therapeutic
dissemination from a uveal melanoma.
An exemplary 25-35 year follow-up report [46] on 302 between 1943-1952 primary enucleated patients with a
posterior uveal melanoma, with a follow-up percentage of 99.8%, revealed that 148 (49%) patients had been
saved from metastatic death. In the intervening decades the figure of 49% should, in theory, have been markedly
improved. Present diagnostic techniques provide earlier detection rates in small melanomas and survival rates
after enucleation depend largely on the volume of the tumour at the time of enucleation. Knowledge that a
malignancy has been removed completely is the predominant factor in the future psychological well being of
many patients.

TTT Plays Role in Ocular Melanoma

by Miriam Karmel Feldman, Contributing Writer
It's still too early to know whether transpupillary thermotherapy (TTT) will become standard treatment for small
choroidal melanomas. Early results show dramatic regression, in which most tumors are reduced to a
nonmeasurable scar within three months. And unlike radiation therapy, which has been the standard therapy for
more than 15 years, TTT may avoid some of the long-term complications that commonly lead to loss of central
vision. Furthermore, TTT is a noninvasive outpatient procedure that can be administered in the office.

Despite promising results, TTT remains an investigational procedure, said Dennis M. Robertson, MD, professor
of ophthalmology at Mayo Clinic and Mayo Medical School. "At the present time I believe there is definitely a
role for transpupillary thermotherapy in the management of small melanomas," said Dr. Robertson, who has
been selectively using TTT since 1996. "But we must use this with a great deal of caution."
In TTT, light from a diode laser is beamed through a dilated pupil to shrink small choroidal melanomas. The first
clinical study of this near-infrared radiation therapy was reported in 1995 by a team of physicians from the
Netherlands. Dr. Robertson, who began his investigation the following year, reported his work on 20 eyes in the
Nov. 1999 issue of Archives of Ophthalmology, along with colleagues Helmut Buettner, MD, and Steven R.
Bennett, MD.
While TTT appears to destroy small tumors and does not seem to produce the complications normally associated
with radiation, including cataract, radiation retinopathy and optic neuropathy, it does have a downside. The
treatment almost always results in a wedge-shaped peripheral field defect. In addition to causing an expected
localized scotoma, occasional unexpected macular abnormalities may occur. What's more, because the laser light
has a limited penetration, it can't be expected to destroy all malignant cells in tumors greater than 2.5 mm thick,
limiting its effectiveness to small tumors.

Selecting Tumor Size

While critics may argue that treating small tumors increases the risk of treating benign tumors, Dr. Robertson
said that in certain circumstances he would rather treat a small growing tumor early with TTT than wait until it
invades the macular region. When that occurs, one has lost the opportunity to destroy the tumor and preserve
central vision. He would also rather treat a small growing lesion before it has reached a thickness where TTT is a
less viable therapy.
Ideally, there will be a way to predict which small tumors are likely to grow. In the report on his early findings,
Dr. Robertson noted that certain recognized risk factors help identify those small melanomas that are likely to
grow, including the presence of lipofuscin, greater tumor thickness and subretinal fluid.

What's Next?
Some early investigators of TTT have suggested combining it with brachytherapy, a form of radiation therapy,
but Dr. Robertson doubts this is a good idea. "If brachytherapy works, why do something else?" he said. Besides,
combining the therapies makes the patient vulnerable to two sets of potential complications.
For now, Dr. Robertson will continue to track his patients and collect data. He is watching to see whether the
tumor has an escape route through the sclera, though he doesn't think that is likely. He is also looking for
recurrence and regrowth, which did occur with earlier promising treatments that didn't pan out, such as argon
laser photocoagulation and xenon arc photocoagulation.
Though he will continue to perform TTT on a highly selective basis, Dr. Robertson urges caution to physicians
who ask him about using the procedure in their practice. This is not a simple treatment, he stated. "I'm not
willing to say more, other than this is a modality that I believe continues to have a role in the management of
selected small tumors."

"Intraocular melanoma" is redistributed by University of Bonn, Medical Center

Intraocular melanoma

GENERAL INFORMATION
Melanoma of the uveal tract (iris, ciliary body, and choroid) is the most common primary ocular cancer in adults.
In patients with small, localized tumors, ocular melanoma is curable, and preservation of vision is possible with
current treatment techniques. However, for patients with posterior uveal melanoma, whether the eye should be
removed or more conservative treatment should be recommended is not known. A major clinical trial funded by
the National Eye Institute, The Collaborative Ocular Melanoma Study, is ongoing.
A number of factors influence prognosis. The most important are size, location, cell type, and extraocular
extension (tumor size is the most critical factor). The selection of treatment depends on the site of origin (the
choroid, ciliary body, or iris); size and location of the lesion; age of the patient; and whether extraocular
invasion, recurrences, or metastases have occurred. These 3 events make the prognosis extremely poor, and
long-term survival cannot be expected. In a group of patients with large posterior uveal melanomas, the
concurrent presence of cytogenetic abnormalities was associated with a poor outcome. In general, the mortality
rate is 46% after 15 years. Most investigators report approximately a 20%-30% 5-year systemic disease
recurrence rate following treatment. Unfortunately, for most patients, the best treatment option is not known, as
appropriate controlled clinical trials have not been performed.
CELLULAR CLASSIFICATION
There is a correlation between cell type and prognosis in intraocular melanomas, especially of the choroid.
Patients with tumors of the spindle cell variety have a better prognosis than those with tumors of the nonspindle
variety.
Cell Type

1. Spindle cell variety

a. Spindle A type
b. Spindle B type
2. Nonspindle cell variety
a. Epithelioid melanomas
b. Mixed cell type melanomas (usually spindle B and epithelioid cells)
c. Necrotic melanoma

STAGE INFORMATION
The uveal tract is divided into 3 regions: the iris, ciliary body, and choroid. Most uveal melanomas occur in the
choroid. The ciliary body is less commonly the site of origin and the iris the least common. Melanomas of the
iris, which are often of the spindle A variety, are relatively slow growing and relatively benign. The major routes
of spread are local extension and by the blood stream. The uveal tract is a vascular structure without lymphatic
channels. When regional lymph node involvement (preauricular, submandibular, and cervical nodes) is seen,
subconjunctival extension of the primary tumor has occurred. Systemic metastases are generally hematogenous
in origin, and the liver is the most common site. Lung and subcutaneous sites are common as well. In
approximately two-thirds of the patients, the liver is the only site of detectable metastasis. In patients with a
history of ocular melanoma who present with hepatic metastases of unknown origin, metastatic melanoma
should be considered in the differential diagnosis. New radiolabeled monoclonal antibody scans may facilitate
detection of extraocular disease, however, these scans are not yet universally available.
Classification by Size
Small: Small ocular melanomas are 2-3 mm or less in elevation*.
Medium: Medium-sized ocular melanomas range from 2-3 mm up to 10 mm in elevation and have a basal
diameter of up to 16 mm.
Large: Large ocular melanomas have a diameter of more than 16 mm or are greater than 10 mm in elevation*.
*In clinical practice, the tumor base may be estimated in average optic disc diameters (dd) (1 dd = 1.5 mm). The
average elevation may be estimated in diopters (3 diopters = 1 mm). Other techniques, such as ultrasonography,
should be used to provide more accurate measurements.
Iris (anterior uvea)
The anterior uveal tract includes the iris. Iris melanomas are relatively benign, slow growing, and rarely
metastasize.
Ciliary body/choroid (posterior uvea)
The posterior uveal tract includes the ciliary body and choroid. The ciliary body is less commonly the site of
origin than the choroid. Melanomas of the posterior uveal tract are cytologically more malignant, are detected
later, and metastasize more frequently than iris melanomas.
Small size:
Small intraocular melanomas are those that are 2-3 millimeters or less in elevation. There is general agreement
that observation to document growth of small melanomas carries little risk.
Medium/large size:
Medium intraocular melanomas are those that are less than 16 millimeters in diameter and between 2-3
millimeters and 10 millimeters in elevation. The therapy of medium-sized intraocular melanomas remains the
most controversial. Large intraocular melanomas are greater than 16 millimeters in diameter or greater than 10
millimeters in elevation and generally require irradiation or enucleation.
Extraocular extension
Uveal melanomas may spread by local extension to involve the retina and vitreous or extend through the sclera
into the orbit or into the optic nerve. Hematogenous metastasis most frequently involves the liver.
IRIS MELANOMA
Iris malignant melanoma is the most common primary neoplasm of the iris and can be most easily seen by the
physician on clinical examination. It is usually a small, discrete lesion, although it may occasionally be diffuse
and infiltrative; multiple; and result in heterochromia, glaucoma, chronic uveitis, or spontaneous hyphema.
Many patients are often aware of a pigmented spot on the iris that has been present for many years and only
recently has begun to grow. With a slit lamp, gonioscopy, and serial slit lamp photography, the ophthalmologist
can document the size and growth of the tumor without biopsy. Fluorescein angiography may be helpful in
demonstrating the vascularity of the lesion, but is not diagnostic. Ultrasonography is of little value in the
evaluation of iris melanoma.
Iris melanoma is relatively benign with a 5-year survival rate of approximately 95%. This is related to the fact
that iris melanomas are predominantly of the spindle A-cell type and are usually smaller in size than posterior
melanoma because of earlier detection. Conservative management is generally advocated whenever possible, but
surgical intervention may be justified with unequivocal tumor growth and with extensive melanomas at initial
examination.
Treatment options:
Standard:
 1. No treatment with careful observation including serial photography (in asymptomatic patients with stable
lesions).

2. With documented growth, excisional surgery:

iridectomy
iridotrabeculectomy
iridocyclectomy (if the ciliary body is involved)
3. Enucleation (in some patients with diffuse involvement of the iris, with involvement of more than one-half of
the iris and anterior chamber angle and documented growth, with extensive iris involvement and intractable
glaucoma, with large unresectable tumors and/or extraocular extension, and with tumors in eyes with no
salvageable vision).

CILIARY BODY AND CHOROID MELANOMA, SMALL SIZE

Melanomas of the choroid and ciliary body are usually diagnosed on clinical examination through the dilated
pupil. Fundus photography is helpful in evaluating nevi and small malignant melanomas and in detecting the rate
of choroidal tumor growth. Fluorescein angiography may show patterns helpful in differentiating melanomas
from other lesions such as choroidal hemorrhage, hemangioma, and metastatic carcinoma. Ultrasonography
shows characteristic patterns that may be diagnostic in differentiating melanomas from other masses. CT
scanning is sometimes used to detect extraocular and optic nerve extension. Magnetic resonance imaging may
prove to be of value.
Tumors of the ciliary body and those close to the optic nervehead seem to have a poorer prognosis than other
choroidal melanomas, but all of them have a poorer prognosis than iris melanomas because they are
cytologically more malignant, detected later, and metastasize earlier.
Prognostic studies of patients with small choroidal melanomas have shown that many small lesions tend to be
dormant and grow slowly with little or no metastatic potential. Furthermore, reports suggest that enucleation
may occasionally result in and/or hasten metastases. This issue remains controversial.
Careful and frequent observation is an option for patients in whom the diagnosis is uncertain or tumor growth is
not documented. Observation is also prudent in asymptomatic patients with stable lesions, particularly elderly or
seriously ill patients, and in patients with tumor growth in their only useful eye. No metastatic death has been
observed in patients with a choroidal melanoma measuring less than 7 x 7 x 2 millimeters.
Traditionally, enucleation has been the conventional treatment of melanoma of the choroid and ciliary body.
However, radioactive ophthalmic applicators using cobalt-60 or iodine-125 have resulted in excellent short-term
survival. Long-term survival data are not yet available from large numbers of patients. Surgery and radiation
techniques have made it possible to save the eye in some patients. External-beam irradiation using charged
particles is used in a few centers. Proton-beam irradiation usually results in radiation maculopathy but
ambulatory vision is preserved in the majority of patients.
The management of posterior uveal melanoma is controversial. A major clinical trial funded by the National Eye
Institute, The Collaborative Ocular Melanoma Study (COMS), is ongoing.
Because there is no agreement concerning the management of small posterior uveal melanomas, investigators in
the COMS will select a treatment, which is often observation, after discussion with the patient. Prospective and
randomized clinical trials are ongoing for patients with medium and large tumors.
Treatment options:
Standard:
1. Careful and frequent observation.

2. Local irradiation with:

cobalt-60 or iodine-125 plaques. Beta irradiation - 106 RU/106 Rh.

proton beam (specialized equipment at Massachusetts General Hospital)
helium ions (specialized equipment at Lawrence Berkley Laboratories)
3. Enucleation.
4. Enucleation with preoperative external-beam irradiation.
CILIARY BODY AND CHOROID MELANOMA, MEDIUM/LARGE SIZE
Melanomas of the choroid and ciliary body are generally diagnosed on clinical examination through the dilated
pupil. Fundus photography is of value in evaluating nevi and small malignant melanomas and in detecting the
rate of choroidal tumor growth. Fluorescein angiography may show angiographic patterns helpful in
differentiating melanomas from other lesions such as choroidal hemorrhage or hemangioma. Ultrasonography
shows characteristic patterns that may be diagnostic in differentiating melanomas from other masses. CT
scanning is sometimes used to detect extraocular and optic nerve extension. Magnetic resonance imaging may
prove to be of value. Cobalt-60, iodine-125, and other ophthalmic plaques can be effective in treatment of
medium-size melanomas.
The role of enucleation in the management of posterior choroidal melanomas is controversial, but enucleation
remains the standard therapy for most large choroidal melanomas and melanomas causing severe glaucoma or
invading the optic nerve. However, reports have shown that enucleation may not result in improved survival and
may actually result in tumor metastases. Use of the "no touch" surgical technique had been proposed to minimize
the risk of tumor cell embolization during enucleation. No-touch enucleation has been abandoned by many
clinicians, as it has never been proven superior to a skilled and gentle enucleation procedure. Preoperative or
postoperative irradiation is a promising approach under evaluation that also could decrease the chances of
precipitating metastases; however, a single study showed no benefit. Advances in radiation techniques have
made it possible to save the eye in selected patients with melanomas that are considered medium to large in size.
Long-term results are not available, and long-term evaluations and analyses show similar survival rates to
enucleation.
In certain centers, charged particle therapy has been applied to choroidal melanomas. This treatment requires
special equipment. The results have been encouraging. Proton-beam irradiation usually results in radiation
maculopathy but ambulatory vision is preserved in the majority of patients.
In some centers, small- and medium-sized tumors have been successfully excised. These operations require
special techniques and instrumentation, and should be performed by specially trained surgeons.
Because the best treatment of patients with medium and large choroidal melanomas is not known, a major
clinical trial funded by the National Eye Institute, The Collaborative Ocular Melanoma Study (COMS), is
ongoing. The COMS investigators think that the study offers the best current treatment approach for eligible
patients. Patients with medium-sized tumors were randomized to receive either radioactive I-125 plaque
treatment or enucleation. Patients with large tumors were randomized to receive enucleation with or without
preoperative external-beam radiation. Recruitment for this portion of the trial was completed in 7/95. No results
of the trial have been announced.
Treatment options:
Standard:
1. Careful and frequent observation is an option for patients in whom the diagnosis is uncertain or tumor
growth is not documented. It is also prudent in asymptomatic patients with stable lesions, in the elderly, in
the seriously ill, and perhaps in patients with tumor growth in their only useful eye.

2. Local irradiation with:

cobalt-60 or iodine-125 plaques. Beta irradiation - 106 RU/106 Rh.

proton beam (specialized equipment at Massachusetts General Hospital)
helium ions (specialized equipment at Lawrence Berkeley Laboratories)
3. Enucleation.
4. Enucleation with preoperative external-beam irradiation.
Under clinical evaluation:
The management of medium and large choroidal melanomas is controversial. Some investigators suggest that
survival following radiation therapy is comparable to survival following enucleation. However, there are
prominent ophthalmologists who disagree. The Collaborative Ocular Melanoma Study (COMS) is a multicenter,
randomized, controlled clinical trial which will compare survival of patients with medium and large choroidal
melanomas with 1 of 2 management strategies. The COMS is supported by the National Eye Institute, and there
are 42 clinical centers in North America.[21,22] Such clinical treatment trials are now justified because the
misdiagnosis rate of choroid melanomas has been decreased to less than 0.5% and in the first report of the
collaborative study, only 5 out of over 1,000 cases were misdiagnosed.[23]

EXTRAOCULAR EXTENSION MELANOMA

Extrascleral extension usually confers a poor prognosis. For patients with gross tumor involvement of the orbit,
treatment requires orbital exenteration often combined with pre- or postoperative radiation therapy. However,
there is no evidence that this radical surgery will prolong life. Most patients with localized or encapsulated
extraocular extension are not exenterated. This subject is controversial.[1-4]
RECURRENT INTRAOCULAR MELANOMA
The prognosis for any patient with recurring or relapsing disease is poor, regardless of cell type or stage. The
question and selection of further treatment depends on many factors, including the extent of the lesion, age and
health of the patient, prior treatment, and site of recurrence, as well as individual patient considerations. Clinical
trials are appropriate and should be considered whenever possible.

INTRAOCULAR MELANOMA - August 1999 - Oncolink

TI - [Transpupillary thermotherapy of choroidal melanoma]
SO - Klin Monatsbl Augenheilkd 1999 Feb;214(2):90-5
PURPOSE: The purpose of this report is to evaluate the efficacy of transpupillary thermotherapy (TTT) to treat
choroidal melanoma. PATIENTS AND METHOD: 17 patients with choroidal melanoma were treated, 6 patients
with small tumors close to posterior pole received TTT only 11 patients were treated simultaneously with TTT
and Ru 106 brachytherapy. To perform TTT a diode laser with a beam diameter of 1.5 to 3 millimeters was used.
Exposure time ranged from 60 to 90 seconds until a light grey appearance of the retinal surface was reached.
Follow-up examinations were performed at 1-month intervals. If the tumor was partially regressed additional
TTT was performed to reach the endpoint of a chorioretinal scar. RESULTS: All tumors exhibited a reduction of
tumor height in a mean follow-up period of 14.25 months. Side effects were minimal. CONCLUSIONS:
Treatment with TTT may be useful as a complementary modality to brachytherapy. A longer follow-up time is
necessary for final evaluation.
TI - Genetic predisposition to ocular melanoma.
SO - Eye 1999;13 ( Pt 1)():43-6
Uveal melanoma is the most common primary intraocular malignancy, with an annual incidence of 6 per
million. The environmental factors known to increase the risk of cutaneous melanoma appear to be less
important in ocular melanoma and it is conceivable that host factors have a greater impact. The coexistence of
ocular and cutaneous melanoma in some patients suggests a predisposition to both types and implicates
mutations in the CDKN2A gene in a proportion of these cases. An association between ocular melanoma and
breast and/or ovarian cancer has also been reported and recent studies of breast cancer families strongly
implicate BRCA2 as a predisposition gene. Other more common genes predisposing to ocular melanoma may be
of low penetrance. An example of a gene in this class is MC1R, which affects host response to ultraviolet
radiation. Identification of genes conferring an increased risk of ocular melanoma should provide insights into
the pathogenesis of this tumour. Furthermore, it offers an opportunity to identify individuals at a high risk who
may benefit from targeted surveillance. At present the identification of such individuals is restricted to the small
number belonging to BRCA2 families and those with the atypical mole syndrome.

Treatment of Metastatic Choroidal Melanoma eye cancer network

by Dr. Bedikian
While standard chemotherapy for metastatic choroidal melanoma may offer prolonged
survival, very few patients have been cured.
Choroidal melanoma tends to metastasize to the liver. In fact, about 85% of metastases will first
present in the liver. This is why your doctor is likely to order liver function studies every 6 months.
Since systemic therapies rarely induce remissions in the liver, most patients survival has not been
improved with most currently available chemotherapy (drug combinations based on treatment of
metastatic cutaneous melanoma).
For a specific patient, the choice of therapy largely depends on the presence or absence of
metastases outside of the liver, the extent of disease within the liver, and its interference in liver
function.
Palliative Surgery: Liver is the predominant site of metastases in a majority of choroidal melanoma
patients. It is (initially) the exclusive site in about 40% of patients. For most patients with liver
metastases, involvement is diffuse or multi-focal and surgery cannot help. For the few patients who
have a slow growing solitary liver metastasis, surgical excision may help. There are several case-
reports in the literature, but no proof that surgery prolongs survival or improves the quality of life of
patients with metastatic choroidal melanoma.
Chemotherapy - Liver Perfusion: With hepatic arterial application of chemotherapy in the M. D.
Anderson Cancer Center only two partial responses were observed among a total of 38 patients
treated. One partial response was observed after intra-arterial infusion of cisplatin combined with
Dacarbazine (DTIC), hydroxyurea and dactinomycin, the other after administration of intra-arterial
Interleukin-2. Both patients received intra-arterial therapy as their first line treatment.
A Phase II study was conducted in western Europe in patients with metastatic choroidal melanoma
confined to the liver. They used the investigational nitrosourea drug Fotemustine administered intra-
arterially to the liver. Four complete and 8 partial responses were seen in 30 patients treated intra-
arterially with fotemustine. Large metastases were resected (as possible) prior to treatment. The
median overall survival time was 14 months, time to hepatic progression was 18 months after
complete and 6.5 months after partial remission.
Carboplatin administered to the liver via hepatic artery resulted in 3 partial responses in 8 treated
patients with a median overall survival of 15 months (ranging 8 to 29 months). In a recent trial
evaluating the activity of isolated hyperthermic hepatic perfusion with Tumor Necrosis Factor (TNF)
alfa and melphalan, among the 7 patients with hepatic metastases from uveal melanoma, 2 complete
responses and 2 partial responses were observed.
Chemo-Embolization: Best results in the therapy of metastatic uveal melanoma confined to the liver
were achieved with chemo-embolization. Forty-four previously untreated patients with liver metastases
were treated with Cisplatin and polyvinyl sponge particles injected intra-arterially to the liver. One
complete response and 15 partial responses (overall Response Rate 36%) were reported. In the pre-
treated group (20 patients) 5 partial responses (RR 25%) were observed. In both groups the chemo-
embolization responders showed a statistically significant longer survival with a median of 14.5
months as compared to the non-responders with a median survival of 5 months. Reversible side
effects included fever, right upper quadrant abdominal pain transient elevation of liver enzymes and
occasionally paralytic ileus lasting no more than 1 to 2 days after the procedure.
Intravenous Chemotherapy: Systemic chemotherapy (somewhat effective in metastatic cutaneous
melanoma) has failed to show activity in uveal melanoma. In a retrospective review of the M. D.
Anderson Cancer Center experience, 129 patients with metastatic choroidal melanoma involving the
liver were treated with systemic chemotherapy (99 patients had no prior history of chemotherapy).
Most of the different multi-drug regimens utilized Dacarbazine. Only one patient showed a partial
response. He was treated with Dacarbazine + BCNU + vincristine + bleomycin. Similarly, review of
therapy results of 51 patients with metastatic uveal melanoma treated on different Eastern
Cooperative Oncology Group melanoma trials showed that none of the 51 responded to the various
chemotherapy regimens used. The results of chemotherapy regimens used for the management of
metastatic uveal melanoma have been summarized in the Table
Table
Results of chemotherapy in metastatic choroidal melanoma
No. of Pts Treatment Response Rate % Resp.
64 DTIC and/or cisplatin 6/64 9
51 CCNU ± DTIC + hydroxyurea, CCNU + BCG or other single agents 0/51 0
51 Various DTIC-based regimens 4/51 8
DTIC + BCNU + Oncovin + Bleomycin ± IFN (BOLD Regimen ±
34 7/34 21
IFN)
18 DTIC + BCNU + cisplatin + tamoxifen (Dartmouth regimen) 1/18 6
18 DTIC+Velban+cisplatin ± IFN ± Tamoxifen 0/22 0
17 DTIC+BCG or C. Parvum 0/17 0
13 TIC+ACT-D ± oncovin ± C. Parvum 0/13 0
8 DTIC, cisplatin, IFN, IL-2 ± vinblastine 1/11 9
*note* Response does not mean cure.
Most of the chemotherapy regimens used with moderate efficacy against cutaneous melanoma have
had marginal efficacy against metastatic choroidal melanoma. Only BOLD-interferon regimen has
show marginal efficacy with a response rate of about 20%. Regional therapies such as intra-hepatic
arterial chemotherapy and chemo-embolization of hepatic metastases with starch particles and
cisplatin have had limited success because two thirds of the patients with metastatic uveal melanoma
have extrahepatic metastases. For this reason patients with metastatic choroidal melanoma are often
excluded from phase II clinical studies evaluating efficacy of new anti cancer drugs against metastatic
cutaneous melanoma.
Biotherapy: Biotherapy means the use of drugs to stimulate the immune system. Though pre-clinical
studies indicated a beneficial effect of interferon (alfa & gamma) on human uveal melanoma cell lines,
clinical data (though limited) failed to show any response of metastatic uveal melanoma. In the M. D.
Anderson Cancer Center trials 14 patients were treated with Interferon (IFN) ± IL-2. Only 2 minor
responses were observed. In a trial with high dose IL-2 in patients with metastatic melanoma, all 7
patients with uveal melanoma with hepatic metastases progressed during IL-2 therapy. In another
study in patients with metastatic melanoma of various primary sites using high dose IL-2 administered
intravenously (7 patients) or into the splenic artery (8 patients) and lymphokine-activated killer (LAK)
cells administered either via the hepatic artery (7 patients) or the portal vein (8 patients), none of the 6
patients with hepatic metastases from uveal melanoma responded.
Investigational Drugs : Since patients with metastatic choroidal melanoma are typically excluded
from phase II studies evaluating new anti-cancer agents for metastatic cutaneous melanoma; certain
investigators have been successful in convincing the pharmaceutical industry about the dire need to
find effective chemotherapy for choroidal melanoma patients.
The following investigational protocols have been initiated:
Dr. Bedikian has 2 ongoing chemotherapy protocols specifically designed for patients with metastatic
choroidal melanoma, one with paclitaxel administered intravenously and the other with 9 Nitro-
Camptothecin taken by mouth. No short or long-term data (response rates) is currently available on
these drugs.

'EMORY RESEARCHERS FIND LASER TREATMENT EFFECTIVE FOR EYE TUMOR

April 1998

Early results from research conducted at the Emory Eye Center show that laser treatment using heat therapy is
effective for treating patients with eye tumors.
Data from the study show that transpupillary thermotherapy (TPTT) effectively can manage small choroidal
melanoma (2.6mm or smaller in thickness).
"This laser treatment was successful for 23 of the 24 patients enrolled in our study," said Antonio Capone, Jr.,
M.D., an Emory retina surgeon and the study's principal investigator. The procedure involves heating the tumor
in 1/10-second bursts with an infrared diode laser. The heat destroys the melanoma cells' metabolism.
In the past, patients with intraocular (within the eye) tumors often were treated with radiation.
"Radiation collapses the tumor mass. It can kill the tumor, but it often 'kills' the vision as well," said Dr. Capone.
"We can destroy the tumor with surgical precision with the laser."
Side-effects are infrequent with TPTT. Researchers have followed the patients enrolled in the study for up to 30
months.
"We still don't know the procedure's effectiveness on tumor-related mortality over the long-term," reports Dr.
Capone. "We will need to follow these patients for five or 10 more years." Dr. Capone's colleague, retina
surgeon Thomas Aaberg, Jr., M.D., also performs the procedure.
TPTT is effective in treating retinoblastoma, a type of retinal tumor that occurs mostly in children.
The Emory Eye Center is one of a few centers on the East Coast and the only one in Georgia with a
comprehensive ophthalmic oncology section. Retina surgeons here have specialized training and experience in
treating patients with ocular melanoma, retinoblastoma and other tumors within the eye. The Eye Center's
ophthalmic pathologist provides analysis and diagnosis of tumors, and its diagnostic center provides the most
advanced technology available to detect tumors. In addition, Emory's oculoplastic surgeons provide plastic,
reconstructive and cosmetic surgery for patients whose eye lids, eye sockets, tear ducts and other eye structures
have been damaged by tumor.
What is choroidal melanoma?
Choroidal melanoma is a collection of abnormal, pigmented cells within the choroid, which is the layer of tissue
in the back of the eye between the retina and sclera (the white of the eye). Choroidal melanoma is the most
common type of primary intraocular tumor in adults. Because this type of tumor occurs inside the eye, it is best
detected early by a thorough annual exam of the back of the eye by an ophthalmologist or optometrist. Unlike
other melanomas, doctors can see the tumor through the pupil of the eye.
Most choroidal tumors grow slowly. The patient may not recognize something is wrong until his or her vision is
impaired by the tumor itself or from retinal detachment or hemorrhaging due to the tumor.
Once diagnosed, ophthalmologists use ultrasonography to classify choroidal melanoma as being small, medium
or large. Small tumors (2.6mm or smaller) have a 20 to 30 percent chance of growing to the point at which the
only treatment is radiation or removal of the eye. In rare instances, the tumor can spread to the lungs, liver or
other major organs, causing death.
Transpupillary thermotherapy (TPTT), a procedure during which an ophthalmologist uses an infrared diode laser
to heat and destroy abnormal cells, is a promising new treatment for small tumors.
###