5
Enucleation Versus Plaque Irradiation for Choroidal Melanoma BRADLEY R. STRAATSMA, MD,t STUART L. FINE, MD,2 JOHN D. EARLE, MD,3 BARBARA S. HAWKINS, MS,2 MARIE DIENER-WEST, PhD,2 JACK A. McLAUGHLIN, PhD,4 THE COLLABORATIVE OCULAR MELANOMA STUDY RESEARCH GROUP Abstract: The Collaborative Ocular Melanoma Study (COMS) is an interna- tional, multicenter-controlled study. The organization includes an. Executive Committee, Steering Committee, 6 Central Units, 32 Clinical Centers, and a Data and Safety Monitoring Committee. Scientifically, the COMS consists of (1) a randomized trial of patients with medium choroidal melanoma treated with enucleation versus iodine-125 plaque irradiation, (2) a randomized trial of pa- tients with large choroidal melanoma treated with enucleation versus preenu- c1eation external beam irradiation and enucleation, and (3) a prospective ob- servational study of patients with small choroidal melanoma to determine whether a randomized trial of treatment is appropriate. In design and conduct of the COMS, special consideration is given to biostatistics and sample size considerations, iodine-125 plaque irradiation of choroidal melanoma, and coor- dinated ocular melanoma research. Recruitment is in progress. However, the pool of eligible patients is limited and the COMS needs the continued support and cooperation of ophthalmologists throughout the United States and Canada. [Key words: choroidal melanoma, cobalt-60, enucleation, iodine-125, iridium- 192, melanoma, plaque irradiation.] Ophthalmology 95:1000-1004, 1988 Management of choroidal melanoma is controversial and unsettled despite more than a century of intense study and extended experience with alternative thera- peutic modalities.l-' Although relatively rare, with ap- proximately 1500 new cases diagnosed in the United States each year, choroidal melanoma is of great impor- Originally received: November 11, 1987. Revision accepted: March 15, 1988. 1 Department of Ophthalmology, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles. 2 Wilmer Institute, Johns Hopkins Hospital, Baltimore. 3 Mayo Foundation, Rochester. 4 National Eye Institute, National Institutes of Health, Bethesda. Presented at the American Academy of Ophthalmology Annual Meeting, Dallas, November 1987. Supported by the National Eye Institute, Bethesda, Maryland. Reprint requests to Bradley R. Straatsma, MD, Jules Stein Eye Institute, UCLA School of Medicine, Los Angeles, CA 90024-1771. 1000 tance in ophthalmology because of its life-threatening capability.Y All available data on choroidal melanoma manage- ment do not establish whether enucleation or plaque irradiation is more effective in prolonging life. 4 ,5 Addi- tionally, there are significant issues related to vision preservation and quality of life. With important ques- tions unresolved by any other method, a clinical trial is warranted. The Collaborative Ocular Melanoma Study (CaMS), supported by the National Eye Institute, is an interna- tional, multicenter-controlled study. It is designed to provide definitive answers to questions concerning ap- propriate treatment for selected patients with choroidal melanoma. The CaMS is in progress at 32 clinical centers. It is directed by the Executive Committee (see Appendix) and Steering Committee and includes six central units (see Appendix). The 32 clinical centers engaged in pa- tient treatment and follow-up care are distributed widely throughout the United States and Canada (Table 1).

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Page 1: Enucleation Versus Plaque Irradiation for Choroidal Melanoma

Enucleation Versus PlaqueIrradiation for ChoroidalMelanomaBRADLEY R. STRAATSMA, MD,t STUART L. FINE, MD,2 JOHN D. EARLE, MD,3BARBARA S. HAWKINS, MS,2 MARIE DIENER-WEST, PhD,2JACK A. McLAUGHLIN, PhD,4 THE COLLABORATIVE OCULARMELANOMA STUDY RESEARCH GROUP

Abstract: The Collaborative Ocular Melanoma Study (COMS) is an interna­tional, multicenter-controlled study. The organization includes an. ExecutiveCommittee, Steering Committee, 6 Central Units, 32 Clinical Centers, and aData and Safety Monitoring Committee. Scientifically, the COMS consists of (1)a randomized trial of patients with medium choroidal melanoma treated withenucleation versus iodine-125 plaque irradiation, (2) a randomized trial of pa­tients with large choroidal melanoma treated with enucleation versus preenu­c1eation external beam irradiation and enucleation, and (3) a prospective ob­servational study of patients with small choroidal melanoma to determinewhether a randomized trial of treatment is appropriate. In design and conduct ofthe COMS, special consideration is given to biostatistics and sample sizeconsiderations, iodine-125 plaque irradiation of choroidal melanoma, and coor­dinated ocular melanoma research. Recruitment is in progress. However, thepool of eligible patients is limited and the COMS needs the continued supportand cooperation of ophthalmologists throughout the United States and Canada.[Key words: choroidal melanoma, cobalt-60, enucleation, iodine-125, iridium­192, melanoma, plaque irradiation.] Ophthalmology 95:1000-1004, 1988

Management of choroidal melanoma is controversialand unsettled despite more than a century of intensestudy and extended experience with alternative thera­peutic modalities.l-' Although relatively rare, with ap­proximately 1500 new cases diagnosed in the UnitedStates each year, choroidal melanoma is of great impor-

Originally received: November 11, 1987.Revision accepted: March 15, 1988.

1 Department of Ophthalmology, Jules Stein Eye Institute, UCLA Schoolof Medicine, Los Angeles.

2 Wilmer Institute, Johns Hopkins Hospital, Baltimore.3 Mayo Foundation, Rochester.4 National Eye Institute, National Institutes of Health, Bethesda.

Presented at the American Academy of Ophthalmology Annual Meeting,Dallas, November 1987.

Supported by the National Eye Institute, Bethesda, Maryland.

Reprint requests to Bradley R. Straatsma, MD, Jules Stein Eye Institute,UCLA School of Medicine, Los Angeles, CA 90024-1771.

1000

tance in ophthalmology because of its life-threateningcapability.Y

All available data on choroidal melanoma manage­ment do not establish whether enucleation or plaqueirradiation is more effective in prolonging life.4,5 Addi­tionally, there are significant issues related to visionpreservation and quality of life. With important ques­tions unresolved by any other method, a clinical trial iswarranted.

The Collaborative Ocular Melanoma Study (CaMS),supported by the National Eye Institute, is an interna­tional, multicenter-controlled study. It is designed toprovide definitive answers to questions concerning ap­propriate treatment for selected patients with choroidalmelanoma.

The CaMS is in progress at 32 clinical centers. It isdirected by the Executive Committee (see Appendix)and Steering Committee and includes six central units(see Appendix). The 32 clinical centers engaged in pa­tient treatment and follow-up care are distributed widelythroughout the United States and Canada (Table 1).

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STRAATSMA et al • CHOROIDAL MELANOMA

Table 1. Clinical Centers

Center

1. W. K. Kellogg Eye CenterAnn Arbor, MI

2. Emory Eye CenterAtlanta, GA

3. Piedmont HospitalAtlanta, GA

4. The Wilmer Ophthalmological InstituteBaltimore, MD

5. Retina Associates, Inc.Boston, MA

6. Illinois Eye and Ear InfirmaryChicago, IL

7. Northwestern University Medical SchoolChicago, IL

8. Cleveland Clinic FoundationCleveland, OH

9. Retina Associates ofCleveland/CaseWestern Reserve UniversityBeachwood, OH

10. Ohio State University College of MedicineColumbus, OH

11 . Texas Retina AssociatesDallas, TX

12. Duke University Eye CenterDurham, NC

13. Hermann Eye CenterHouston, TX

14. The University of Iowa Hospitals andClinicsIowa City, IA

15. Estelle Doheny Eye FoundationLos Angeles, CA

16. Jules Stein Eye InstituteLos Angeles, CA

Principal Investigator Center Principal Investigator

Vine 17. Southern California Permanente Group HayrehPanorama City, CA

Meredith 18. Universityof Wisconsin ChandraMadison, WI

Jarrett 19. North Shore University Hospital PackerManhasset, NY

Schachat 20. Bascom Palmer Eye Institute OlsenMiami, FL

Trempe 21 . Medical College of Wisconsin Eye Institute MielerMilwaukee, WI

Goldberg 22. Cornell University AbramsonNew York, NY

Puklin 23. Retina-Vitreous Consultants RinkoffPittsburgh, PA

Zakov 24. Oregon Health Sciences University WatzkePortland, OR

Rice 25. Oregon Lions Sight & Hearing Institute ChenowethPortland, OR

26. Mayo Foundation RobertsonDavidorf Rochester, MN

27. Associated Retinal Consultants, P.C. MargherioFuller Royal Oak, MI

28. Washington University School ofMedicine SmithDutton SI. Louis, MI

29. University ofTexas Health Science Center van HeuvenRuiz San Antonio, TX

30. Northern California Choroidal Melanoma SchatzWeingeist Associates

San Francisco, CA31 . Scott & White Cl inic Dieckert

Ryan Temple, TX32. Princess Margaret Hospital, The Ontario Fitzpatrick

Straatsma Center InstituteToronto, Canada

Additional important components of the study are theData and Safety Monitoring Committee (see Appendix)and Mortality Coding Committee.

The primary outcome for the COMS is overall sur­vival after melanoma treatment. Prolongation of life isthe most important factor. Secondary outcomes are me­tastasis-free survival, cancer-free survival, and preserva­tion of vision.

In scientific design, the COMS consists of two ran­domized trials and one prospective observational study.The first randomized trial is for patients with mediumchoroidal melanoma, with tumor thickness measuringfrom 3 to 8 mm in height and up to 16 mm in largestbasal diameter. These patients are assigned randomly totreatment by enucleation or by iodine-l 25 plaque irra­diation. After treatment, each patient is scheduled forfollow-up evaluation by the ophthalmologist at leastevery 6 months and by the oncologist at least annuallyfor 10 years or until death.

The second randomized trial is for patients with largechoroidal melanoma, with tumor thickness measuringgreater than 8 mm in height or greater than 16 mm inlargest basal diameter. These patients are assigned ran­domly to treatment by enucleation or by enucleationpreceded by 20 Gy of external beam irradiation in five

divided doses. After treatment, each patient is scheduledfor follow-up evaluation by the ophthalmologist at 6­month intervals and by the oncologist annually for 10years or until death.

The prospective observational study is for patientswith small choroidal melanoma, with tumor thicknessmeasuring from 1 to 3 mm in height and at least 5 mmin largest basal diameter. These patients are beingtreated according to preferences of the treating ophthal­mologist and the patient. At the end of a 2-year period,data will be reviewed to determine the appropriatenessof a randomized trial for patients with small choroidalmelanoma.

Design and conduct of the COMS raised issues uniqueto this multicenter-controlled trial. These factors in­cluded biostatistics and sample size considerations, io­dine-125 plaque irradiation of choroidal melanoma,and coordinated ocular melanoma research.

BIOSTATISTICS AND SAMPLE SIZECONSIDERATIONS

Analysis of choroidal melanoma mortality data pre­sented in 64 reports published between 1966 and 1986

1001

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OPHTHALMOLOGY • JULY 1988 • VOLUME 95 • NUMBER 7

6000

COORDINATED OCULAR MELANOMARESEARCH

The CaMS provides an exceptional opportunity forcoordinated studies related to ocular melanoma. Among

50

50

40

40

30

30

Medium Tumors

20

Large Tumors

20

1 0

10

6000

5000

4000

Total3000

patients

required

2000

1000

00

5000

4000

Total3000

patients

required

2000

1000

00

% Difference inmortality

Fig 1. Medium-sized choroidal melanomas. Effect on sample size ofdetectable differences in mortality using a 5-year mortality rate of 30%,a type I error of 1% (alpha = 0.0 I), and a type 2 error of 10% (beta= 0.10).

% Difference inmortality

Fig 2. Large-sized choroidal melanomas. Effect on sample size of de­tectable differences in mortality using a 5-year mortality rate of 50%, atype I error of I% (alpha = 0.0 I), and a type 2 error of 10% (beta= 0.10).

ration, plaque placement, and patient contact while theplaque is in place.

demonstrated wide variability in the completeness ofreports.! Using all available complete data, the best esti­mates of the 5-year mortality rate after enucleationalone are approximately 30% for medium tumors andapproximately 50% for large tumors."

Using these estimates and assuming a type I error ofI%(alpha = 0.01; i.e., the probability of finding a differ­ence when there really is none) and a type 2 error of 10%(beta = 0.10; i.e., the probability of not finding a differ­ence when there really is one), sample sizes were calcu­lated for medium and large melanomas (Figs 1,2).4

Furthermore, if we postulate that a 25% difference inmortality rate would be clinically significant, a samplesize of 2400 medium melanomas is needed. For largetumors with a greater mortality rate, a sample size of1000 large melanomas is necessary.

If a type 1 error of 5% and a type 2 error of 20% areassumed, the sample sizes for medium melanomas andlarge melanomas are decreased substantially.

Recruitment of study patients is ongoing. Even in thisinitial phase, 70% of all eligible patients are enrolling inthe CaMS randomized trials. This is a highly favorableenrollment.

Recruitment of study patients is certain to be an ex­tremely important consideration throughout this study,because choroidal melanoma is a rare condition. Unlikemany other clinical trials, the pool of potential patientsis very small and a number of these are ineligible forrandomization because of concurrent eye disease, dis­qualifying systemic disease, or other factors. In recogni­tion of these aspects, recruitment of patients for theCaMS may extend for 8 to 10 years.

Iodine-125 was selected for the CaMS after carefulconsideration of all available isotopes." Cobalt-60, irid­ium-l92, and iodine-125, for example, are photonemitters (gamma rays or x-rays) but they differ in theenergy of the emitted radiation, the relative penetrationof tissue, and the thickness of material required forshielding. In clinical practice, the relative quantity ofiodine-125, iridium-l92, and cobalt-60 can be adjustedto obtain the same dose rate at a distance of 10 mm. At adistance of 15 mm, the dose from iodine-125 is only 5%less than the dose from cobalt-60 (Fig 3). This reductionin iodine-125 dose may be beneficial in decreasing radi­ation to normal ocular tissues.

Although dose distribution in the treatment zone issimilar for iodine-125 and cobalt-60, there is an impor­tant difference in ability to shield the emitted radiation(Fig 4). To reduce the radiation from cobalt-60 by 50%,a 12-mm thickness of lead is required. The radiationfrom iodine-125 is reduced to 0.1% by a 0.5-mm thick­ness of gold.

Iodine-125 plaques used in the CaMS are shaped likea smooth bottle cap. Normal structures lateral to andbehind the plaque are effectively shielded. Additionally,the ability to readily shield iodine-125 is important forradiation protection of personnel during plaque prepa-

IODINE-125 PLAQUE IRRADIATION OFCHOROIDAL MELANOMA

1002

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STRAATSMAet al • CHOROIDAL MELANOMA

Fig 3. Normalized curves(at 10 mm using single seedof rad ioisotope) demon­strating that radiation dosesare nearly identical withthree radiation sources upto 15 mm, at which depththe radiation from iodine­125 begins to decrease.

192

8 10 12 14 16 18 20 22 24

Depth , mm

642

Iodine

10(0.1)

1 (0.01)

100 (1.0)

O.1 (0.001) L..-.....L..----I_....I...----L_....&.---J._...I..---L._..L..--.L._L.-~

o

(I,)-t13a:(I,)enoCl(I,)>

'';::t13Q)a:

Fig 4. Schematic diagram of isodose lines from iodine-125 and cobalt­60 therapeutic plaques, both delivering 100 Gy to apex of choroidalmelanoma 7 mm in height. A I-mm spacer separates iodine-I 25 seedsfrom sclera.

these are opportunities for an extended or even lifelongstudy of COMS patients who may move but will con­tinue to be followedby one of the 32 clinical centers, forsociologic assessment of quality of life in treated pa­tients, for determination of costs associated with treat­ment, and for the use of new and as yet undeveloped

Iodine 125 Cobalt 60 modalities for diagnosis, treatment, and follow-up thatdo not disrupt the COMS. With these and many otheropportunities for coordinated scientific studies, theCOMS is a resource for advancement of knowledge andimprovement of ophthalmologic patient care.

APPENDIX

Collaborative Ocular Melanoma StudyExecutive Committee

Stuart L. Fine, MD, Chairman; Bradley R. Straatsma,MD, Co-chairman; John D. Earle, MD, Co-chairman;Daniel M. Albert, MD; Sandra Frazier Byrne; MarieDiener-West, PhD; Peter Fitzpatrick, MB, BS; WilliamF. Hanson, PhD; Barbara S. Hawkins, MS; Jan A. Mar­kowitz, PhD; Lee McCaffrey,MA; Jack A. McLaughlin,PhD; William F. Mieler , MD; Samuel Packer, MD;Dennis M. Robertson, MD; Marvin Rotman, MD; An­drew P. Schachat, MD; Frances Walonker, CO, COMT;Thomas A. Weingeist, MD, PhD; James K. V. WillsonIII, MD.

Collaborative Ocular Melanoma Study Central Units

Chairman's Office, Stuart L. Fine, MD, The WilmerOphthalmological Institute , The Johns Hopkins Medi­cal Institutions, Baltimore, Maryland; Coordinat ingCenter, Barbara S. Hawkins, MS, The Wilmer Ophthal­mological Institute, The Johns Hopkins Medical Insti­tutions, Baltimore, Maryland; Photograph ReadingCenter, Thomas A. Weingeist, MD, PhD, Departmentof Ophthalmology, University ofIowa, Iowa City, Iowa;Echography Center, Sandra Frazier Byrne , BascomPalmer Eye Institute, University of Miami, Miami,Florida; Radiological Physics Center, William F. Han­son, PhD, M. D. Anderson Hospital and Tumor Insti­tute, Houston , Texas; Pathology Center, Daniel M. Al­bert, MD, Department of Ophthalmology, Massachu­setts Eye and Ear Infirmary, Boston, Massachusetts.

1003

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OPHTHALMOLOGY • JULY 1988 • VOLUME 95 • NUMBER 7

Data Safety and Monitoring Committee

Matthew D. Davis, MD, Chairman; Thomas E. Davis,MD; James Eltringham, MD; Frederick L. Ferris III,MD; J. Donald M. Gass, MD; Lael C. Gatewood, PhD;Robert J. Levine, MD; Robert W. Makuch, PhD.

REFERENCES

1. Donders PC. Malignant melanoma of the choroid. Trans OphthalmolSoc UK 1973; 93:745-51.

2. Ruiz RS. Early treatment in malignant melanomas of the choroid. In:Brockhurst RJ, Boruchoff SA, Hutchinson BT, Lessell S, eds. Contro-

1004

versy in Ophthalmology. Philadelphia: WB Saunders Co, 1977;604-10.

3. Strickland D, Lee JAH. Melanomas of eye: stability of rates. Am JEpidemiol1981; 113:700-2.

4. Diener-West M, Hawkins BS, Fine SL. Collaborative Ocular Mela­noma Study: challenges in designing and conducting a clinical trial ofa rare condition. ARVO Abstracts. Invest Ophthalmol Vis Sci 1987;28(Suppl):393.

5. Markowitz JA, Hawkins BS, Diener-West M, et al. Quality of publishedreports on mortality from choroidal melanoma, 1966-1986. ARVOAbstracts. Invest Ophthalmol Vis Sci 1987; 28(Suppl):105.

6. Earle J, Kline RW, Robertson DM. Selection of iodine 125 for theCollaborative Ocular Melanoma Study. Arch Ophthalmol 1987;105:763-4.