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Journal of Clinical Oncology, Vol 22, No 7 (April 1), 2004: pp. 1293-1300 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.08.140 Determinants of Outcome in Melanoma Patients With Cerebral MetastasesFrom the Sydney Melanoma Unit, Departments of Radiation Oncology and Neurosurgery, Royal Prince Alfred Hospital; and Department of Surgery, University of Sydney, Sydney, New South Wales, Australia. Address reprint requests to John F. Thompson, MD, Sydney Melanoma Unit, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW 2050, Australia; e-mail: john.thompson{at}email.cs.nsw.gov.au
PURPOSE: To analyze prognostic factors, effects of treatment, and survival for patients with cerebral metastases from melanoma. PATIENTS AND METHODS: All melanoma patients with cerebral metastases treated at the Sydney Melanoma Unit between 1952 and 2000 were identified. From 1985 to 2000, patients were diagnosed and treated using consistent modern techniques and this cohort was analyzed in detail. Multivariate analysis of prognostic factors for survival was performed. RESULTS: A total of 1,137 patients with cerebral metastases were identified; 686 were treated between 1985 and 2000. For these 686 patients, the median time from primary diagnosis to cerebral metastasis was 3.1 years (range, 0 to 41 years). A total of 646 patients (94%) have died as a result of melanoma. The median survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years). Treatment was as follows: surgery and postoperative radiotherapy, 158 patients; surgery alone, 47 patients; radiotherapy alone, 236 patients; and supportive care alone, 210 patients. Median survival according to treatment received for these four groups was 8.9, 8.7, 3.4, and 2.1 months, respectively; the differences between surgery and nonsurgery groups were statistically significant. On multivariate analysis, significant factors associated with improved survival were surgical treatment (P < .0001), no concurrent extracerebral metastases (P < .0001), younger age (P = .0007), and longer disease-free interval (P = .036). Prognostic factors analysis confirmed the important influence of patient selection on treatment received. CONCLUSION: This large series documents the characteristics of patients who developed cerebral metastases from melanoma. Median survival was dependent on treatment, which in turn was dependent on patient selection.
Cerebral metastases are a common and distressing consequence of melanoma, and are ultimately diagnosed in up to 10% of patients.1 Cerebral metastases are found at autopsy in 49% to 73% of those who die as a result of melanoma.2,3 Indeed, melanoma is one of the most common underlying diagnoses in patients with cerebral metastases, after lung and breast cancer.4 Management of cerebral metastases in melanoma patients depends on several factors. Selection for surgery is usually on the basis of having a single surgically accessible metastasis with absent or stable extracerebral metastases, and good performance status (unless this is reduced because of a reversible neurologic deficit from the tumor). In many centers postoperative radiotherapy is given routinely. Patients not selected for surgery may be offered palliative radiotherapy for symptom relief, using either conventional whole-brain radiotherapy (WBRT) or stereotactic methods. Those who exhibit poor performance status or who refuse radiotherapy may be managed with corticosteroids and other supportive measures. The aims of this study were to obtain survival data from the largest group of patients with melanoma-related cerebral metastases yet reported, and to identify major prognostic factors that might help in the planning of treatment strategies in individual patients.
Patients diagnosed with cerebral metastases were identified from the database of the Sydney Melanoma Unit (SMU; Sydney, Australia), which contains details of more than 21,000 patients treated since 1952. Those treated from 1985 to 2000, and those treated before 1985, were analyzed separately. 1985 was selected because computed tomography scanning became readily available in our institution at that time, and also because the same medical personnel have been involved in the care of SMU patients since 1985. The databases of the neurosurgery and radiation oncology departments of the Royal Prince Alfred Hospital were also examined independently. They were cross-checked with patients from the SMU database and the results combined. Every effort was made to retrieve details of treatment by surgery and radiotherapy, performed not only at Royal Prince Alfred Hospital (Sydney, Australia) but also at other hospitals. The following information was obtained: age, sex, date of primary melanoma diagnosis, Breslow thickness, presence of extracranial metastases, number of cerebral metastases (one or more than one), radiotherapy dose, and details of surgery. Information on survival and cause of death was obtained from the databases, hospital records, general practitioners' records, and state cancer registries as necessary.
Statistical Analysis
A total of 1,137 patients with cerebral metastases treated at the SMU from 1952 to 2000 were identified. Of these, 451 patients were diagnosed between August 1952 and December 1984, and 686 were diagnosed between January 1985 and June 2000. The following analysis is based on the latter cohort of 686 patients. The majority of them (85%) had a history of cutaneous melanoma, 1% had a history of mucosal melanoma, and 14% had an occult primary tumor. In 6.7% of patients cerebral metastases were present at the time of initial diagnosis of melanoma (primary or metastatic), and in four patients (0.6%) cerebral metastases were the only known site of melanoma. Patient characteristics are listed in Table 1. Treatments received, together with median survival times, are listed in Table 2. Surgery (performed in 205 patients in the 1985 to 2000 cohort) comprised craniotomy with macroscopically complete excision in the great majority of patients, or a subtotal resection or biopsy when this was not achievable. In most cases, surgery was offered to patients with a single, surgically accessible metastasis or with stable or absent extracerebral metastases, but occasionally it was offered to patients with two or three metastases if one was considered life threatening. An overlapping cohort of SMU patients who were treated with craniotomy and postoperative radiotherapy from 1979 has been reported previously.8
In the 1985 to 2000 cohort, the total number of patients receiving radiotherapy was 394, of whom 158 had previously had a craniotomy. Palliative WBRT was offered to patients with reasonable performance status who had symptomatic cerebral metastases but who were not considered to be candidates for surgery. WBRT was given as parallel opposed lateral portals, using a 4- or 6-MV photon linear accelerator in most cases. The dose range was 4 to 60 Gy, the majority of patients receiving 20 Gy in five daily fractions (111 patients) or 30 Gy in 10 daily fractions (123 patients). Patients having adjuvant WBRT after surgery received a boost to the excision site. Thirty-one patients underwent stereotactic radiotherapy, 11 of these after a previous craniotomy; most of the patients also received WBRT. As of June 2003, 646 of the 686 patients in the 1985 to 2000 cohort (94%) had died as a result of melanoma, 17 patients (2.5%) were alive with no sign of melanoma recurrence, and eight patients (1.2%) were alive with melanoma. Seven were alive but their status was unknown. Seven patients had died as a result of causes other than melanoma, and one had died as a result of an unknown cause. The median overall survival from the time of diagnosis of cerebral metastasis was 4.1 months (range, 0 to 17.2 years; Fig 1). Survival at 6 months was 37%, survival at 1 year was 19%, and survival at 5 years was 4%. Differences in median survival among each of the four treatment groups are shown in Table 2 and Figure 2. Univariate analysis showed that patients treated with surgery (with or without postoperative radiotherapy) had a statistically significant longer survival than those treated with supportive care or radiotherapy alone (P < .001). Patients treated with radiotherapy alone also had a statistically significant longer survival than those treated with supportive care alone (P < .001). There were no significant survival differences between the surgery and radiotherapy versus surgery-alone groups (P = .21).
Results of the multivariate analysis of possible prognostic factors are shown in Table 3, and indicate that treatment received and the presence of concurrent metastases were the most important predictors of survival. Prognosis was marginally better for patients who were younger at the time of diagnosis of cerebral metastases or who had a longer interval between their melanoma diagnosis and the diagnosis of cerebral metastases.
Patient selection factors were influential on the median survival times for different treatment groups. To examine this further, we analyzed the relationship between treatment received and possible prognostic factors (Table 4). This confirmed that patients were selected for active treatment on the basis of having a single cerebral metastasis, cerebral metastases with no evidence of metastatic disease elsewhere, or a younger age. Analysis of 5-yearly cohorts between 1985 and 2000 showed no significant change in practice over this time.
The cohort of 451 patients diagnosed between August 1952 and December1984 was analyzed separately. Patient characteristics are listed in Table 1 and survival according to treatment is listed in Table 2. Information on the number of cerebral metastases was obtained by various methods other than computed tomography (including carotid arteriography, air encephalography, and surgical or autopsy findings). The overall median survival of this cohort was only 2.5 months. Survival at 6 months was 22%, survival at 1 year was 10%, and survival at 5 years was 2%. A much higher proportion of patients (74%) were treated with supportive care only. The small number of patients treated with surgery and radiotherapy had a median survival of 11.5 months.
This large series of 1,137 melanoma patients with cerebral metastases was studied using prospectively collected information from one of the world's longest established melanoma databases. Cerebral metastases were diagnosed in approximately 6% of all patients recorded on the SMU database, although the true risk of a patient with melanoma developing a cerebral metastasis may be lower because of referral bias to this specialist center. No attempt was made to collect or analyze details of performance status, corticosteroid treatment, or investigations because of the unreliability of such data in a retrospective study spanning several decades. Likewise, whether a patient had received adjuvant or palliative immunotherapy or chemotherapy was not recorded because these treatment modalities were thought unlikely to have materially influenced survival in the great majority of patients with cerebral metastases. Other studies have addressed these matters in more detail, including two that examined cohorts of patients from the SMU.8,9 It is of interest to compare our results for the 686 patients treated between 1985 and 2000 with those of a study of 702 patients with melanoma-related cerebral metastases treated at Duke University Medical Center (Durham, NC).1 The characteristics of these patients were compared with those of 6,251 melanoma patients who did not develop cerebral metastases. It was found that those developing metastases were more likely to be male; to have a primary site on the trunk, head and neck region, or mucosa; and to have a thick or ulcerated primary tumor. In our study 26% of patients had a head and neck primary, 28% had a limb primary, 29% had a primary on the trunk, and in 14% the primary was occult, compared with 15%, 48%, 32%, and 4%, respectively, for the SMU database overall. Thus, we too found a preponderance of patients with head and neck primaries, but did not confirm a preponderance of trunk primaries. Limb primaries, on the other hand, were associated with a markedly reduced likelihood of developing cerebral metastases. In the study reported by Sampson et al,1 the median time from the diagnosis of primary melanoma to the diagnosis of cerebral metastases was 3.7 years, exactly the same as in our series. Survival according to treatment received was also similar to that in our series (Table 5).
An analysis of prognostic factors in a large series of 1,292 patients with cerebral metastases from breast cancer, lung cancer, melanoma, and other primary sites was reported by Lagerwaard et al.4 As in our study of exclusively melanoma metastases, treatment modality had the greatest impact on survival (Table 5). Other significant favorable prognostic factors identified on multivariate analysis were good performance status, no systemic tumor activity, normal serum lactate dehydrogenase, age younger than 70 years, and a breast cancer primary site. Lagerwaard et al4 also examined other studies that have used multivariate analysis and found that the most consistently significant prognostic factors were treatment received, systemic disease activity, and performance status. Survival for patients with cerebral metastases from melanoma is remarkably similar to survival for patients with cerebral metastases from other primary malignancies (Table 5). For patients considered unsuitable for surgical resection in our series, survival was generally poor: only 2.1 months for patients who received neither surgery nor radiotherapy and 3.4 months for those treated with radiotherapy alone (P < .001). These figures are similar to those reported by Sampson et al (Table 5).1 To what extent the longer median survival compared with supportive care is related to radiotherapy itself or to selection of patients with better performance status is unclear; no randomized trials have been conducted of radiotherapy versus best supportive care. However, our analysis confirms that significant patient selection bias occurs (Table 4). The Radiation Therapy Oncology Group in the United States proposed three prognostic groups based on recursive partitioning analysis of their trials of radiotherapy for cerebral metastases.10 The best prognostic group (with a median survival of 7.1 months) comprised patients who were younger than 65 years of age, had a controlled primary tumor, cerebral metastases only, and a good Karnofsky performance score (70 or more). Median survival was 2.3 months if the Karnofsky performance score was less than 70 and 4.2 months in all other patients. A palliative benefit from radiotherapy is reported in approximately 50% of patients and another benefit is that it may allow for a reduction in corticosteroid dose.11–13 The literature contains reports of several series of patients treated with palliative radiotherapy specifically for melanoma-related cerebral metastases,14–19 including a cohort of 129 patients from the SMU.9 An improved response with increasing radiation dose was suggested by one study17 but not by others.15,16 Median survival times were similar in these studies, ranging from 2.2 to 5.3 months depending on the patient population, and an improved outcome was seen for those treated with surgery as well as radiotherapy.9,14–17 In our series, patients who received surgery were almost invariably selected for this form of treatment on the basis of limited intracerebral and extracerebral disease and reasonable neurologic function. Single cerebral metastases are not uncommon: in an autopsy series of 954 patients with cerebral metastases, 40% had a single metastasis, 27% had two or three lesions, and 33% had four or more lesions.20 Magnetic resonance imaging studies show single metastases in one fourth to one third of patients.21 In our study, median survival was similar for the 158 patients who received adjuvant postoperative radiotherapy and for the 47 patients who had surgery alone (Table 2; Fig 2). However, significantly improved survival for patients receiving adjuvant postoperative radiotherapy was shown in the series of melanoma patients with cerebral metastases reported by Sampson et al1 (702 patients) and Skibber et al22 (34 patients), and in a series of patients with cerebral metastases from any primary site reported by Smalley et al23 (85 patients). In two other studies of melanoma patients, however, no improvement in survival was demonstrated in patients receiving postoperative radiotherapy.24,25 Owing to differences in patient selection criteria, randomized studies are clearly necessary to resolve the question of whether radiotherapy improves survival after surgery for cerebral metastases. In one such study, 95 patients with a single cerebral metastasis from any primary site were randomized after surgery to observation or WBRT (50.4 Gy in 28 fractions).26 Although the risks of cerebral recurrence and neurologic death were found to be significantly less in the group treated with adjuvant radiotherapy, there was no improvement in overall survival. However, a 5-week course of radiotherapy was used, which many physicians would view as inappropriate in the palliative setting, and the power of the trial was low because patient numbers were small. Three randomized trials have addressed the issue in another way, by posing the question, "Does surgery provide any additional benefit over radiotherapy in patients with single cerebral metastases?" Two trials showed a survival benefit for combined surgery and radiotherapy compared with radiotherapy alone,27,28 and one showed no difference.29 In our study, stereotactic radiotherapy was used to treat 31 patients, 11 of whom had also had surgery. The median survival of this highly selected group was 8.9 months, consistent with other, similar series of melanoma patients.30,31 In an analysis of 122 patients with a single cerebral metastasis from a variety of primary tumor types treated with WBRT plus a stereotactic boost, a survival rate similar to that of historical controls treated with surgery and radiotherapy was reported.32 Median survival was 11 months, the 1-year actuarial local control rate was 85%, and excellent local control was observed for melanoma patients in particular. It is possible that more aggressive treatment may also be of benefit to patients with more than one cerebral metastasis. A small randomized study of WBRT versus WBRT with a stereotactic radiotherapy boost in patients with two to four cerebral metastases showed improved local control in the boosted group,33 although survival was not significantly different. Nonrandomized studies suggest an increased local recurrence rate after stereotactic radiotherapy when WBRT is omitted,34–36 and some also show worse survival.37,38 Randomized studies are in progress to elucidate some of these uncertainties and to try to improve the outcome for appropriately selected patients. A Radiation Therapy Oncology Group trial in patients with one to three cerebral metastases from any primary tumor type randomly assigns patients to WBRT with or without a stereotactic boost. In an ongoing Eastern Cooperative Oncology Group study in the United States, patients with a single metastasis are randomly assigned to surgery or stereotactic radiotherapy; those with two to three metastases have stereotactic radiotherapy and are then randomly assigned to WBRT or observation.39 The results of this study suggest that appropriately selected patients may benefit from aggressive treatment for intracerebral metastases. It is hoped that appropriately powered randomized trials currently in progress will elucidate this area further, given that the randomized trials to date have been small and therefore inconclusive. It is possible that the patients treated aggressively have improved survival as a result of lead-time bias, and merely present with symptoms early in the course of their metastatic cerebral disease. The data presented in this analysis nevertheless support the current treatment policies at the SMU for patients with cerebral metastases. Those with a single cerebral metastasis and no progressive systemic disease are treated with surgery and postoperative WBRT. Stereotactic radiotherapy is given to selected patients with surgically inaccessible lesions. In those considered unsuitable for surgery or stereotactic radiotherapy, a short course of conventional WBRT is given if the patient is symptomatic and considered fit enough for treatment; otherwise, palliation with corticosteroids is recommended.
The authors indicated no potential conflicts of interest.
We acknowledge the statistical assistance provided by Drs Mark Woodward and Sing Kai Lo, Institute for International Health, Sydney, and John Simes, National Health and Medical Research Council Clinical Trials Centre, University of Sydney.
Supported by the Melanoma Foundation of the University of Sydney and the Melanoma and Skin Cancer Research Institute. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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7. Tarone RE, Ware J: On distribution-free tests for equality of survival distributions. Biometrika 64:156–160, 1977 8. Zacest AC, Besser M, Stevens G, et al: Surgical management of cerebral metastases from melanoma: Outcome in 147 patients treated at a single institution over two decades. J Neurosurg 96:552–558, 2002[Medline] 9. Stevens G, Firth I, Coates A: Cerebral metastases from malignant melanoma. Radiother Oncol 23:185–191, 1992[CrossRef][Medline] 10. Gaspar L, Scott C, Rotman M, et al: Recursive partitioning analysis of prognostic factors in three RTOG brain metastases trials. Int J Radiat Oncol Biol Phys 37:745–751, 1997[CrossRef][Medline] 11. Bezjak A, Adam J, Panzarella T, et al: Radiotherapy for brain metastases: Defining palliative response. Radiother Oncol 61:71–76, 2001[CrossRef][Medline] 12. Bezjak A, Adam J, Barton R, et al: Symptom response after palliative radiotherapy for patients with brain metastases. Eur J Cancer 38:487–496, 2002 13. Borgelt B, Gelber R, Kramer S, et al: The palliation of brain metastases: Final results of the first two studies by the radiation therapy oncology group. Int J Radiat Oncol Biol Phys 6:1–9, 1980[Medline] 14. Katz H: The relative effectiveness of radiation therapy, corticosteroids and surgery in the management of melanoma metastatic to the central nervous system. Int J Radiat Oncol Biol Phys 7:897–906, 1981[Medline] 15. Ziegler J, Cooper J: Brain metastases from malignant melanoma: Conventional vs. high-dose-per-fraction radiotherapy. Int J Radiat Oncol Biol Phys 12:1839–1842, 1986[Medline] 16. Rate W, Solin L, Turrisi A: Palliative radiotherapy for metastatic malignant melanoma: Brain metastases, bone metastases, and spinal cord compression. Int J Radiat Oncol Biol Phys 15:859–864, 1988[Medline] 17. Isokangas O, Mulhonen T, Kajanti M, et al: Radiation therapy of intracranial malignant melanoma. Radiother Oncol 38:139–144, 1996[CrossRef][Medline] 18. Seegenschmiedt M, Keilholz L, Altendorf-Hofman A, et al: Palliative radiotherapy for recurrent and metastatic malignant melanoma: Prognostic factors for tumour response and long-term outcome: A 20-year experience. Int J Radiat Oncol Biol Phys 44:607–618, 1999[CrossRef][Medline] 19. Ellerhorst J, Strom E, Nardone E, et al: Whole brain irradiation for patients with metastatic melanoma: A review of 87 cases. Int J Radiat Oncol Biol Phys 49:93–97, 2001[CrossRef][Medline] 20. Pickren J, Lopez G, Tsukada Y, et al: Brain metastases: An autopsy study. Cancer Treat Symptoms 2:295–313, 1983 21. Yuh W, Engelken J, Mulhonem M, et al: Experience with high-dose gadolinium in the evaluation of brain metastases. Am J Neuroradiol 13:335–345, 1992[Abstract] 22. Skibber J, Soong S, Austin L, et al: Cranial irradiation after surgical excision of brain metastases in melanoma patients. Ann Surg Oncol 3:118–123, 1996[Abstract] 23. Smalley S, Schray M, Laws E, et al: Adjuvant radiation therapy after surgical resection of solitary brain metastasis: Association with pattern of failure and survival. Int J Radiat Oncol Biol Phys 13:1611–1616, 1987[Medline] 24. Wronski M, Arbit E: Surgical treatment of brain metastases from melanoma: A retrospective study of 91 patients. J Neurosurg 93:9–18, 2000[Medline]
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26. Patchell R, Tibbs P, Regine W, et al: Postoperative radiotherapy in the treatment of single metastases to the brain: A randomized trial. JAMA 280:1485–1489, 1998 27. Noordijk E, Vecht C, Haaxma-Reiche H, et al: The choice of treatment of single brain metastasis should be based on extracranial tumour activity and age. Int J Radiat Oncol Biol Phys 29:711–717, 1994[Medline] 28. Patchell R, Tibbs P, Walsh J, et al: A randomised trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494–500, 1990[Abstract] 29. Mintz A, Kestle J, Rathbone M, et al: A randomised trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 78:1470–1476, 1996[CrossRef][Medline] 30. Mingione V, Oliveira M, Prasad D, et al: Gamma surgery for melanoma metastases in the brain. J Neurosurg 96:544–551, 2002[CrossRef][Medline] 31. Mori Y, Kondziolka D, Flickinger JC, et al: Stereotactic radiosurgery for cerebral metastatic melanoma: Factors affecting local disease control and survival. Int J Radiat Oncol Biol Phys 42:581–589, 1998[CrossRef][Medline] 32. Auchter R, Lamond J, Alexander E, et al: A multiinstitutional outcome and prognostic factor analysis of radiosurgery for resectable single brain metastasis. Int J Radiat Oncol Biol Phys 35:27–35, 1996[CrossRef][Medline] 33. Kondziolka D, Patel A, Lunsford L, et al: Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases. Int J Radiat Oncol Biol Phys 45:427–434, 1999[Medline] 34. Flickinger J, Kondziolka D, Lunsford L, et al: A multi-institutional experience with stereotactic radiosurgery for solitary brain metastasis. Int J Radiat Oncol Biol Phys 28:797–802, 1994[Medline] 35. Fuller B, Kaplan I, Adler J, et al: Stereotaxic radiosurgery for brain metastases: The importance of adjuvant whole brain irradiation. Int J Radiat Oncol Biol Phys 23:413–418, 1992[Medline] 36. Sneed PK, Lamborn KR, Forstner JM, et al: Radiosurgery for brain metastases: Is whole brain radiotherapy necessary? Int J Radiat Oncol Biol Phys 43:549–558, 1999[CrossRef][Medline] 37. Pirzkall A, Debus J, Lohr F, et al: Radiosurgery alone or in combination with whole brain radiotherapy for brain metastases. J Clin Oncol 16:3563–3569, 1998[Abstract] 38. Suh J, Barnett G, Miller D, et al: Is whole brain radiation therapy needed for all patients with newly diagnosed brain metastases undergoing stereotactic radiotherapy? Int J Radiat Oncol Biol Phys 39:226, 1997 (suppl 1) 39. Shaw E: Radiotherapeutic management of multiple brain metastases: "3000 in 10" whole brain radiation is no longer a "no brainer." Int J Radiat Oncol Biol Phys45:253–254, 1999[Medline] Submitted August 21, 2002; accepted January 27, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test for categoric variables and the Wilcoxon rank sum test for continuous variables. 
