Survival in Metastatic Ocular Melanoma

S. RAJPAL, MD,' R. MOORE, MS,t AND C. P. KARAKOUSIS, MD'

Of 35 patients with metastatic ocular melanoma, 71.4% manifested liver involvement either initially (45.7%) or later in the course of the disease (25.7%). With liver involvement, the median survival was 2.2 months, whereas with pulmonary involvement it was 19.2 months after the first evidence of met- astatic disease (P < 0.01). Survival after recurrence varied also with age, those younger than 50 years having median survival of 14 months, with those 50 years or older having median survival 3.5 months (P c 0.01). It also varied with the patient's sex, males having median survival 3 months after recurrence, and females 10.4 months (P < 0.05). Younger patients and females had also longer disease-free intervals prior to recurrence. Surgical removal of metastases, when feasible, in combination with chemotherapy, seems to offer improved palliation, since a subsequent median survival thus of 18.4 months was observed with 3/15 patients alive disease-free 1 to 3 years later, while the median survival of 20 patients not treated with surgery was 2.5 months. Most of this difference in survival, however, is due to a difference in tumor load between the two groups, with patients subjected to surgery having lesser amounts of tumor and/or more favorable sites.

Cancer 52334-336, 1983.

CULAR MELANOMA represents a distinct variety of 0 malignant melanoma because of the peculiarities posed for the diagnosis and treatment of the primary site and the distinct pattern of metastasis observed with this lesion.

This report presents the experience at Roswell Park Memorial Institute in the last 15 years with patients admitted with this diagnosis.

Materials and Methods

Forty-six patients with history of ocular melanoma were seen in the period from January 1966 to January 1980. Of these, 29 patients were male and 17 female, and all of the patients were white. The anatomic site of the primary lesion in 38 patients with accurately spec- ified location was the choroid in 36 patients, ciliary body in one, the iris in one. The left eye was involved in 25 patients, while the right eye was involved in 2 I . The site of the primary was less than 10 mm in diameter in 6 patients and greater than 10 mm in 22 patients; it was not recorded in 18.

The primary was treated by enucleation in 38, by exenteration in three, partial excision in one, and ra-

From the *Departments of Surgical Oncology and TBiostatistics. New York State Department of Health, Roswell Park Memorial In- stitute, Buffalo, New York.

Address for reprints: C. P. Karakousis, MD, Department of Surgical Oncology, Roswell Park Memorial Institute, 666 Elm Street, Buffalo, NY 14263.

Accepted for publication April 12, 1982.

diation or photocoagulation in four patients. All treat- ment of the primary sites was rendered in other centers.

Nine of the patients referred have remained disease- free, one is alive with disease, one died of other causes, without evidence of recurrence of melanoma, and 35 patients referred had or developed metastatic disease. These patients constitute the subject of this report. The median time to recurrence was 28 months (range, 0- 173 months).

The organs involved by metastatic disease are de- picted in Table 1. Twenty-two of the patients received chemotherapy, with decarbazine (DTIC) (4 patients), nitrosoureas (3 patients), a combination of DTIC and nitrosoureas (6 patients) or other drugs (9 patients). Twenty of the patients with metastatic disease had no surgery, while 15 patients had surgical treatment.

Standardized life tables utilizing the Breslow method were used to evaluate the results.'

Results

Nine patients who did not develop metastases have had median survival 146.4 months, whereas 35 patients with metastases had total median survival 36.7 months (P < 0.001). In the latter group of patients, the median time prior to recurrence was 28.5 months, whereas the median survival after recurrence was 8.2 months.

Survival after recurrence varied according to the first organ involved with metastases; 15 patients with liver involvement initially had a median survival of 2.2 months; six patients with lung metastases had a median survival of 19.2 months; three patients with extensive

0008-543)</83/07 I5/0334 $0.95 0 American Cancer Society

334

No. 2 METASTATIC OCULAR MELANOMA - Rajpal et al. 335

TABLE I . Metastases in Ocular Melanoma

Clinical incidence (35 Cases)

Organ

~~

Initial organ Subsequent Autopsy incidence involvement involvement Total (33 Cases)

No. % No. B No. YO No. ?k

Liver Lung Subcutaneous tissue skin Bone Lymph nodes GI tract Brain Other

45.7 17.1 8.6 2.9 8.6 2.9 2.9 8.6

25.7 22.9 25.7 14.3 5.7

11.4 2.9

11.6

25 14 12 6 5 5 2 7

7 I .4 40.0 34.3 17.1 14.3 14.3 5.7

19.2

24 17 4 8

12 9 8

12

72.7 51.5 12.1 24.2 36.4 27.3 24.2 36.4

lymph node and subcutaneous metastases had a median survival of 2 months: and three patients with subcuta- neous metastases only had a median survival of 14 months. The difference in survival between the patients with liver versus lung metastases was highly significant (P < 0.00 I) . Twenty-five patients who manifested liver metastases during the course of their illness, with or without other organ involvement, had a median survival of 3 months, whereas four patients who did not develop clinical evidence of liver metastases during the entire course of their disease had a median survival 15 months (P < 0.01).

Among the patients with recurrence, 12 patients younger than 50 years old had median survival after recurrence of 14.0 months, whereas 2 1 patients 50 years or older had median survival of 3.5 months (P < 0.01). The median time prior to recurrence in the younger group was 73 months (range, 26-173 months), whereas in the older group it was 17 months (range, 0-44 months), a significant difference (P < 0.00 1).

Twenty male patients and 15 female patients had a median time prior to recurrence of 25 and 37 months, respectively. After recurrence, the median survival was 3.0 months for males and 10.4 months for females (P < 0.05). The difference in survival between the sexes after recurrence persisted within each age group, sug- gesting that sex and age are independent variables. In the younger age group, median survival for males and females was I 1.5 and 18 months, respectively, whereas in the older age group, median survival was 2.0 and 4.9 months, respectively (P < 0.01).

The poorer prognosis of liver involvement compared to other sites appears to be also a variable independent of sex or age, since it persisted within the subgroups according to each of these two parameters. The median survival following recurrence for liver involvement ver- sus other organ involvement was, respectively: for males, 2.25 versus 8 months; for females, 7.5 versus 21; for

those younger than 50 years, 9.5 versus 15: and for those older than 50 years, 1.9 versus 4 months.

The disease-free interval prior to recurrence did not affect significantly subsequent survival in this series. Fifteen patients with a disease-free interval less than 24 months had a median survival of 7 months, whereas 20 patients with a dibease-free interval of 24 months or longer had a median survival of 7.3 months after re- currence. This lack of difference in survival could not be accounted for by a difference between the two groups in age, sex, or organ involvement.

Of the four patients treated with DTIC, one showed greater than 50% regression and one showed stabiliza- tion; one of the six patients treated with DTIC and ni- trosoureas showed disease stabilization, whereas 19 pa- tients had tumor progression on chemotherapy. The three patients with regression or stabilization had a me- dian survival of 14 months, while 19 patients with pro- gression had a median survival of 7 months. Further- more, the 22 patients who received chemotherapy had a median survival of 8.9 months, whereas 13 patients without chemotherapy had a median survival of 1.7 months.

Median survivals for patients were as follows: four patients who had surgical treatment, 10 months: 1 I who had chemotherapy alone, 4.5 months; 1 1 patients with surgery and chemotherapy, 19.5 months. These 15 pa- tients with surgical treatment had a median survival of 18.4 months, whereas 20 patients without surgical treat- ment had a median survival of 2.5 months. Of the pa- tients who received surgical treatment, seven had partial removal of the tumor for palliation of symptoms (three patients) or regional chemotherapy to the liver with or without ligation of the hepatic artery (four patients). Eight patients with resection of all gross tumor had a mean survival of 24.25 months (range, 12-42 months); three of these patients had pulmonary metastases (one of them with bilateral lung lesions removed remains

336 CANCER July15 1983 Vol. 52

disease-free at 36 months), whereas four patients had subcutaneous metastases (one disease-free at 12 months), and one patient a large omental and sigmoid colon metastasis (disease-free at 30 months).

Discussion

Ocular melanomas have a distinct tendency to me- tastasize to the liver. Thus about 60% of the patients have liver involvement either exclusively2 or with other organs3 as the initial manifestation of metastatic disease. In some series, hepatic involvement during the entire course of the illness among patients with metastatic re- currence has been reported to be 98%.4 This high fre- quency of hepatic involvement with primary ocular m e l a n ~ m a , ~ contrasts with the reported incidence of 4%6.7 to 139b8 upon the initial diagnosis of recurrence among patients with recurrent melanoma from a pri- mary cutaneous site.

In autopsy series of deaths from malignant melanoma of cutaneous primary site, the liver was the third site, in frequency, involved by metastatic disease, whereas among deaths from metastatic ocular melanoma, the liver was the most common site of metastasis and, in contrast to cutaneous melanoma in which exclusive in- volvement was noted only in 1.5%, it was exclusively involved in almost one third of the patients at autopsy.'

The interval between enucleation and onset of met- astatic disease was reported, in one series, to be 3.4 years in men and 5.5 years in women, significantly differ en^^ The mean interval between the onset of metastatic dis- ease and death was 1.3 years3 The median time from enucleation to hepatic metastases in another series was 43 months while the survival from onset of metastatic spread was 7 months8

In the current series, 7 1.4% of the patients developed clinical evidence of liver metastases, which was followed in frequency by pulmonary in 40% and subcutaneous tissue-skin involvement in 34.3% (Table I).

For the patients who developed recurrence, the overall median survival was 36.7 months and that following recurrence 8.2 months. Survival varied according to the first organ involved, patients with liver involvement hav- ing poorer survival compared to those with pulmonary metastases.

Patients younger than 50 years old had an improved survival after recurrence and a longer disease-free inter- val compared to that of patients 50 years or older. Fe-

male patients had an improved survival after recurrence, and a longer disease-free interval compared to males. The improved survival in females has been previously reported. ' O . ' '

Liver involvement, age and sex appeared to be in- dependent variables in the present series whereas the disease-free interval prior to recurrence did not signifi- cantly affect subsequent survivals.

Of 22 patients treated with chemotherapy one patient exhibited greater than 50% regression and two patients stabilization and had a median survival of 14 months, whereas 19 patients manifested progression with a me- dian survival of 7 months. The 22 patients who received chemotherapy had a median survival of 8.9 months, whereas ten patients without chemotherapy had a me- dian survival of 1.7 months. The difference in survival, however, between these two groups may be due largely to selection of patients, in the sense that patients ter- minally ill were not considered suitable for chemo- therapy.

Combination of modalities, i.e., surgical removal of the tumor plus chemotherapy in these patients, where applicable, seems to offer improved palliation. However, combination of modalities was applied to a group with more favorable prognosis. Patients chosen for surgical treatment had generally lesser amounts of tumor, and in only four of I5 there was initially liver involvement.

REFERENCES

1 . Breslow N. A generalized Kruskal: Wallis test for comparing K samples subject to unequal patterns of censuring. Biometrika 1970; 57:579-594.

2. Einhorn LH, Burgess MA, Gottlieb JA. Metastatic patterns of choroidal melanoma. Cancer 1974: 34: 1001-1004.

3. Chaz DH. Metastatic choroidal melanoma. Am J Ophthalmol

4. Shields JA. Current approaches to the diagnosis and manage- ment of choroidal melanomas. Sun, Ophthalmol 1977; 21:443.

5. Lee YTN. Malignant melanoma: Pattern of metastasis. Cancer J Clinicians 1980; 30: 137- 157.

6. Das Gupta T, Brasfield R. Metastatic melanoma: A clinicopath- ological study. Cancer 1964; 17:1323-1339.

7. Stehlin JS, Hills WJ, Ruffino C. Disseminated melanoma: Bio- logic behavior and treatment. Arch Surg 1967; 94:495-501.

8. Einhorn LH, Burgess MA, Vallejos C ef a/. Prognostic correla- tions and response to treatment in advance metastatic melanoma. Cancer Res 1974; 34: 1995-2004.

9. Patel JK. Didolkar MS, Pickren WJ, Moore RH. Metastatic pat- tern of malignant melanoma: A study of 2 I6 autopsy cases. Am J Surg 1978; 135:807-810.

10. DeVita V T Jr, Fisher RI. Natural history of malignant mela- noma as related to therapy. Cancer Treaf Rep 1976; 60:153-157.

I I . Rampen FHJ. Mulder JH. Malignant melanoma: An androgen- dependent tumour? Lancet 1980: 1:562-564.

1978; 86~76-80.