Download Legacy of the Collaborative Ocular Melanoma Study

CLINICAL TRIAL RETROSPECTIVE
SECTION EDITOR: SIMMONS LESSELL, MD
The articles that follow are part of an ongoing series that aims to review collaborative prospective studies supported by the National Eye
Institute. The first article, written by investigators, will remind readers of the rationale, goals, methods, findings, and recommendations.
The second article, written by an expert who did not participate in the investigations, will offer a constructive critique and attempt to estimate
the impact of the study on the practice of ophthalmology.
Legacy of the Collaborative Ocular Melanoma Study
Bertil Damato, MD, PhD, FRCOphth
Z
IMMERMAN ET AL1 CAUSED MUCH CONSTER-
nation when in the 1970s they suggested that
enucleation of eyes with uveal melanoma accelerated metastatic death by disseminating tumor cells into the general circulation.
Their hypothesis was based on the peak in mortality in
the second postoperative year. Around the same time, Manschot and van Strik2 declared that radiotherapy of uveal
melanoma was unjustifiable because histology frequently demonstrated viable melanoma cells in irradiated eyes. Studies reporting no significant differences in
survival between enucleation and radiotherapy were unconvincing because they were nonrandomized with inadequate patient numbers and short follow-up. The “Zimmerman-Manschot debate” stirred much controversy about
the treatment of choroidal melanoma, unsettling both patients and ophthalmologists. For these reasons, it was entirely reasonable to undertake large, collaborative studies
that would provide definitive answers on how survival and
quality of life are influenced by enucleation, preenucleation radiotherapy, and brachytherapy.
For editorial comment
see page 965
The Collaborative Ocular Melanoma Study (COMS)
has done truly impressive work in successfully performing large, randomized, prospective studies. The data are
highly credible, thanks to excellent compliance with protocols and near-perfect diagnostic accuracy.
The trial of enucleation alone vs pre-enucleation radiotherapy included 1003 patients with large choroidal
melanoma and concluded that there was no difference
between treatment arms.3 This COMS study is so convincing that any conflicting results from smaller, nonrandomized evaluations of pre-enucleation radiotherapy are disregarded.4 Enucleation is now performed
without the expense of adjuvant radiotherapy. Financial savings should exceed the cost of the COMS investigation. This negative finding confounds Zimmerman’s
hypothesis, reassuring patients and their ophthalmoloAuthor Affiliations: Ocular Oncology Service, Royal Liverpool
University Hospital, Liverpool, England.
gists that enucleation does not accelerate death from metastatic disease.
Another influential COMS conclusion was that in 1317
patients with medium-sized choroidal melanoma, the
5-year mortality with histopathologically confirmed melanoma metastasis after brachytherapy with iodine 125 was
no worse than after enucleation.5 This provided reassurance that brachytherapy is “as safe as enucleation.” Eyes
saved as a result of COMS conclusions should quickly
outnumber eyes enucleated in the study if this has not
already happened.
The number of patients enrolled in the COMS is a remarkable achievement, considering the rarity of uveal
melanomas. However, neither of the randomized studies provides sufficient statistical power to state that there
is no survival difference between rival treatments. In the
brachytherapy study, for example, the 95% confidence
intervals for unadjusted risk ratios were excessively wide
(ie, 0.86-1.24 for all-cause mortality and 0.81-1.41 for
histopathologically confirmed metastasis during the 12year follow-up).5 In addition, many would not be satisfied that brachytherapy is as effective as enucleation unless they are reassured that local recurrence does not
increase mortality; however, the COMS did not address
this question. Furthermore, since the ocular treatments
essentially aimed to prevent metastatic spread, the significance of the COMS results was diminished by the fact
that in the brachytherapy and pre-enucleation radiotherapy studies, at least 10% and 35% of patients, respectively, died within 5 years of treatment and hence
as a result of preexisting systemic disease, if calculations based on uveal melanoma doubling times are accepted.6,7 Finally, the follow-up times, although impressive, were perhaps insufficient to detect differences
between treatments in preventing metastasis. A metaanalysis of breast cancer patients indicates that an adverse effect of local treatment failure on mortality takes
about 15 years to become evident statistically.8 Few COMS
patients were followed up for 10 years and there is little
power to detect differences in this area of the survival
curves. The reassurance provided by COMS is not as statistically sound as one might like.
The COMS would probably have reached exactly the
same conclusions even if the sample sizes and follow-up
were sufficient. Basic science research elsewhere has re-
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vealed that uveal melanomas develop nonrandom chromosomal abnormalities such as monosomy 3, which correlate strongly with mortality.9,10 These findings support
the hypothesis that there are 2 subtypes of uveal melanoma: high-grade melanomas, which are all fatal because
they metastasize before treatment of the primary tumor,
and low-grade melanomas, which grow slowly without ever
metastasizing, even if untreated. There is growing suspicion that with medium and large uveal melanomas, ocular treatment is only palliative and that it is only with small
tumors that there is any hope of preventing metastasis. In
concentrating on medium-sized and large tumors, the
COMS may have backed the wrong hypothesis regarding
the time of onset of metastatic spread of melanoma from
the eye. Future studies evaluating how ocular treatment
influences survival should ideally focus on patients with
a “small” melanoma, in whom any opportunities for preventing or delaying metastatic disease are greatest.
Unfortunately, we cannot identify clinically the minority of small melanomas that are life-threatening and we
do not know when high-grade tumors start to metastasize. Patients with a “good melanoma” are therefore overtreated, unnecessarily sacrificing vision and the eye, whereas
those with “bad” tumor may be treated only belatedly, perhaps after preventable metastatic spread has occurred.11
The COMS observational results will help design future
investigations addressing the management of small melanocytic tumors of uncertain metastatic potential.12
In view of the profound prognostic differences between low-grade and high-grade uveal melanomas, some
form of tumor grading at the time of initial treatment
should ideally be performed routinely, as happens with
other cancers. Routine grading would enhance the evaluation of ocular treatments with respect to ocular and systemic outcomes and should reduce the number of patients required for such studies. Grading would probably
involve routine biopsy, which should stimulate interest
in histological and cytogenetic markers of tumor grade.
The COMS pathological investigation of 1527 eyes with
uveal melanoma provides much information on the histology of these tumors.13 Such data would become more
meaningful if correlated with survival. This tissue bank
and the accompanying survival data could prove invaluable in validating markers of tumor grade.
The COMS publications on ocular and psychological
outcomes after brachytherapy and enucleation are important additions to the literature, especially because the data
originate from many independent treatment centers. The
brachytherapy with iodine 125 was followed by high rates
of visual loss, enucleation, and local treatment failure so
that any initial gains in quality of life vis-à-vis enucleation diminished over time.14-16 The COMS concluded that
this analysis allows individual patients and their physicians to make informed choices regarding treatment based
on personal preferences; however, quality of life was not
measured in relation to factors such as tumor size and location, visual acuity in each eye, and the development of
any complications. Furthermore, one wonders whether
ocular morbidity after brachytherapy was caused by the
choice of plaque isotope (ie, iodine 125) or whether it reflected the surgeons’ inexperience in centers treating small
numbers of patients (no slur intended as internationally
most patients with uveal melanoma are treated by surgeons who administer brachytherapy infrequently). In any
case, I hope that these COMS results will encourage future investigations comparing brachytherapy with iodine
125 with brachytherapy with ruthenium 106 as well as with
proton beam and stereotactic radiotherapy. Future evaluations of patient care should take into account the fact that
more centers now offer a wide range of therapies, which
allows for selecting the best treatment and combining different modalities to improve results.
There is scope for more studies, such as treatment of
juxtapapillary melanomas, iris melanomas, and melanomas with extraocular extension, not to mention adjuvant systemic therapy in high-risk patients. Thanks to
the COMS, participating clinicians in many centers have
learned how to define and measure variables and outcomes in a uniform manner. In addition, ophthalmic researchers have gained vast experience in conducting multicenter studies.17 Measures are required urgently to
preserve this precious COMS know-how. It would be ideal
if perpetual collaborative studies could be undertaken,
routinely categorizing all patients and following every patient until death. Multicenter collaboration would also
help participating centers improve their own standards
of care by comparing their outcomes with those of other
centers, anonymously or otherwise.
The COMS may not have answered the (possibly unanswerable) question, “Do I take the eye out or leave it
in?”; however, it has provided a wealth of knowledge and
information yet to be fully reaped. This reminds me of
the fable about a farmer who told his sons that they would
find a treasure in a neglected field. They did not unearth
any gold, but having dug up the entire ground, they decided to raise a crop and were rewarded by a bumper harvest more valuable than the trove they imagined.
Submitted for Publication: November 28, 2006; accepted November 29, 2006.
Correspondence: Bertil Damato, MD, PhD, FRCOphth,
Ocular Oncology Service, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, England (bertil
@damato.co.uk).
Financial Disclosure: None reported.
Additional Contributions: I thank Ian Campbell, Sarah
Coupland, Carrol Gamble, Tero Kivelä, William R. Lee,
Jacob Pe’er, and Stefan Suciu for their advice.
REFERENCES
1. Zimmerman LE, McLean IW, Foster WD. Does enucleation of the eye containing
a malignant melanoma prevent or accelerate the dissemination of tumour cells.
Br J Ophthalmol. 1978;62(6):420-425.
2. Manschot WA, van Strik R. Is irradiation a justifiable treatment of choroidal melanoma? analysis of published results. Br J Ophthalmol. 1987;71(5):348-352.
3. Hawkins BS. The Collaborative Ocular Melanoma Study (COMS) randomized trial
of pre-enucleation radiation of large choroidal melanoma, IV: ten-year mortality
findings and prognostic factors. COMS report number 24. Am J Ophthalmol. 2004;
138(6):936-951.
4. Kilic E, Stijnen T, de Jong PT, et al. Reduced melanoma-related mortality in uveal
melanoma by preenucleation radiotherapy. Arch Ophthalmol. 2005;123(10):
1363-1367.
5. Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma, V: twelve-year mortality rates
and prognostic factors. COMS Report No. 28. Arch Ophthalmol. 2006;124(12):
1684-1693.
6. Manschot WA, van Strik R. Uveal melanoma: therapeutic consequences of doubling times and irradiation results: a review. Int Ophthalmol. 1992;16(2):91-99.
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7. Eskelin S, Pyrhonen S, Summanen P, Hahka-Kemppinen M, Kivela T. Tumor doubling times in metastatic malignant melanoma of the uvea: tumor progression
before and after treatment. Ophthalmology. 2000;107(8):1443-1449.
8. Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the
extent of surgery for early breast cancer on local recurrence and 15-year survival:
an overview of the randomised trials. Lancet. 2005;366(9503):2087-2106.
9. Prescher G, Bornfeld N, Hirche H, Horsthemke B, Jockel KH, Becher R. Prognostic implications of monosomy 3 in uveal melanoma. Lancet. 1996;347(9010):
1222-1225.
10. Scholes AG, Damato BE, Nunn J, Hiscott P, Grierson I, Field JK. Monosomy 3 in
uveal melanoma: correlation with clinical and histologic predictors of survival.
Invest Ophthalmol Vis Sci. 2003;44(3):1008-1011.
11. Straatsma BR, Diener-West M, Caldwell R, Engstrom RE. Mortality after deferral
of treatment or no treatment for choroidal melanoma. Am J Ophthalmol. 2003;
136(1):47-54.
12. Collaborative Ocular Melanoma Study Group. Factors predictive of growth and
treatment of small choroidal melanoma: COMS Report No. 5. Arch Ophthalmol.
1997;115(12):1537-1544.
13. Collaborative Ocular Melanoma Study Group. Histopathologic characteristics of
uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma
Study: COMS report No. 6. Am J Ophthalmol. 1998;125(6):745-766.
14. Melia BM, Abramson DH, Albert DM, et al. Collaborative ocular melanoma study
(COMS) randomized trial of I-125 brachytherapy for medium choroidal melanoma, I: visual acuity after 3 years. COMS report No. 16. Ophthalmology. 2001;
108(2):348-366.
15. Jampol LM, Moy CS, Murray TG, et al. The COMS randomized trial of iodine 125
brachytherapy for choroidal melanoma, IV: local treatment failure and enucleation in the first 5 years after brachytherapy. COMS report No. 19. Ophthalmology.
2002;109(12):2197-2206.
16. Melia M, Moy CS, Reynolds SM, et al. Quality of life after iodine 125 brachytherapy vs enucleation for choroidal melanoma: 5-year results from the Collaborative Ocular Melanoma Study. COMS QOLS Report No. 3. Arch Ophthalmol. 2006;
124(2):226-238.
17. Diener-West M, Hawkins BS. Changing current practice: implementing large multicenter trials for a rare condition. Appl Clin Trials. 2002;11(9):48-54.
The Investigators’ Perspective on the Collaborative
Ocular Melanoma Study
Stuart L. Fine, MD; Barbara S. Hawkins, PhD
I
N THE LATE 1970S AND EARLY 1980S, US OPHTHAL-
mologists who diagnosed uveal melanoma in a patient confronted a difficult decision: whether to
recommend enucleation of the eye with the tumor, in accord with a century of ophthalmic practice, or to refer the patient to one of a small number of ophthalmologists who were advocating eye-conserving
radiotherapy for many such tumors. The dilemma was exacerbated by reports regarding a large series of patients who
had undergone enucleation that showed that the period
with the highest incidence of death was 1 to 2 years following enucleation.1-3 Also, although of lesser concern with
decreasing rates of misdiagnosis, the ophthalmologist had
to consider the possibility of removing an eye that harbored not melanoma but a benign mass. Thus, the ophthalmologist had to choose between 2 options: remove the
affected eye and possibly hasten the patient’s death (or discover a misdiagnosis) or refer the patient for radiotherapy and possibly hasten his or her death should radiotherapy prove to be less effective than enucleation to
control the tumor and avoid metastasis.4,5
As survival data from uncontrolled series of patients
treated with eye-conserving radiotherapy accumulated
and comparisons were made to historical series of patients whose tumors were treated with enucleation,6-8 the
available evidence suggested that enucleation and radiotherapy were equally effective (or equally ineffective, depending on one’s point of view) with respect to prolonging life. However, because of the retrospective nature of
the comparisons and differences in the characteristics
of patients and tumors selected for enucleation and radiotherapy, most ophthalmologists in the United States
remained uncertain regarding the best course for their
Author Affiliations: Scheie Eye Institute, University of
Pennsylvania, Philadelphia (Dr Fine); Wilmer Eye Institute, The
Johns Hopkins University, Baltimore, Maryland (Dr Hawkins).
patients. Furthermore, the location of the largest clinical practices specializing in radiotherapy for uveal melanoma on the Atlantic and Pacific coasts meant that most
patients who elected eye-conserving radiotherapy incurred significant expenses.
During a series of meetings of retinal specialists, a consensus gradually emerged that a scientifically valid prospective study was needed of comparable cases of uveal
melanoma, some of whom were treated with enucleation and others by eye-conserving radiotherapy. However, the appropriate design of such a study was debated at length. Several meetings were held in 1984 to
design a study, with most ophthalmologists and biostatisticians advocating a randomized clinical trial. A key
meeting was held in Bethesda, Maryland, in December
1984 under the auspices of the National Eye Institute of
the National Institutes of Health with the goal of reaching consensus on the design of one or more randomized
trials. At that time, the 2 methods of eye-conserving radiotherapy for which the largest experience was available were charged particles (either protons or helium ions)
and brachytherapy via an episcleral radioactive plaque.
DESIGN ISSUES AND DECISIONS
Decisions to be made during the design of the Collaborative Ocular Melanoma Study (COMS) included the number of clinical trials to be conducted, the method(s) of delivering radiotherapy and the number of treatment arms
in each trial, and the difference in mortality rates between
treatment arms that would lead to a preference for one treatment over the other if a difference of that magnitude were
observed. Initially, 3 randomized trials were considered,
one each for large, intermediate, and small choroidal melanoma. Consensus rapidly was achieved regarding the design and treatment arms for randomized trials for large and
“medium-sized” tumors. However, the risk of misdiagnosis was believed to be high in small tumors, with many pos-
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