Melanoma-induced brain metastases

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Melanoma-induced brain metastases Expert Rev. Anticancer Ther. 8(5), 743–755 (2008)

Robert R McWilliams†, Ravi D Rao, Jan C Buckner, Michael J Link, Svetomir Markovic and Paul D Brown †

Author for correspondence Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Tel.: +1 507 284 8432 Fax: +1 507 284 1803 [email protected]

Brain metastases are a common site of metastasis from malignant melanoma, and are associated with a poor prognosis. Diagnosis of brain metastasis may also have significant implications for quality of life, and management can be difficult due to rapid progression of disease and resistance to conventional therapies. In this article, we will review the published evidence for treatment modalities for melanoma-induced brain metastases and outline future directions for research. In brief, surgical management of solitary or acutely symptomatic lesions appears to alleviate symptoms and provide the possibility of local control of disease. Stereotactic radiosurgery is an increasingly utilized technique for patients with a limited number of metastases, and presents a less invasive alternative to craniotomy. External-beam radiation alone appears effective in palliating symptoms. Chemotherapy alone is relatively ineffective, though combined chemotherapy with external-beam radiation is being investigated. Future directions include combined-modality therapy, the incorporation of novel agents, and careful consideration of the structure of clinical trials for this disease. KEYWORDS: brain • melanoma • metastases • radiosurgery • treatment

Metastasis to the brain is a devastating and frequent consequence of metastatic melanoma. From autopsy series, it has been reported that 50–75% of those who die from melanoma have evidence of metastatic disease in the CNS [1,2]. A majority of patients (two-thirds) are symptomatic and diagnosed prior to death [3], however, in a significant minority, the metastases are clinically silent. Many patients, especially those with multiple metastases, will remain dependent on corticosteroid therapy until death [4]. Diagnostic testing for brain metastases is often prompted by symptoms such as confusion (45%), headache (27%), focal motor or sensory deficits (47%) or seizures (11%) [3]. Contrastenhanced CT scans and MRI are standard methods for imaging the CNS in order to confirm the diagnosis. However, MRI is more sensitive than CT scanning [5] and is, therefore, the preferred modality when possible [6,7]. As the use of FDG-PET becomes increasingly routine as follow-up for patients with melanoma, some metastases are discovered using this modality, although the resolution for brain metastases is insufficient for this to be used as an imaging study for brain metastases [8]. Although characteristic appearance and a clinical setting of advanced melanoma are often sufficient for www.expert-reviews.com

10.1586/14737140.8.5.743

diagnosis, a biopsy to confirm melanoma should be performed if the radiographic and clinical picture strongly suggest an alternative diagnosis. Historically, the prognosis of patients with brain metastases is largely poor, with median survival ranging from 2.8–4.0 months after diagnosis in the general population [3,4,9]. A large proportion (20–55%) of patients with metastatic melanoma will die as a result of their brain metastases [2,4,10]. Attempts have been made to stratify patients with brain metastases from melanoma according to prognostic variables, in order to be able to compare study populations, make treatment decisions, and offer prognostic advice to patients. The best described prognostic system is the recursive partition analysis (RPA) derived by the Radiation Therapy Oncology Group (RTOG) from pooled data from three consecutive prospective randomized trials, which categorizes patients into risk categories using Karnofsky Performance Score (KPS), status of extracranial disease, and age of the patient. Patients falling into Class 1 (age 1 met N = 23) 84 147 Zacest (2002)

56

[40]

NR NR 47 4.4 NR NR 5.0 months 84 Konstadoulakis 32 (2000)

NR

[33]

14.2 95 47 8.8 44 47 6.7 months 37 76 Wronski (2000) 91

[21]

8.6 (includes life-threatening morbidity) 93 NR 12.1 NR NR 8.2 months NR 85 139 Sampson (1998)

n with solitary n with Median survival Deaths from Recurrence of Long-term Median Symptoms at Deaths within Ref. metastases extracranial after resection brain brain metastases survivors age presentation 30 days of (%) disease (%) metastases (%) after surgery (%) (>3 years) (years) (%) surgery (%)

Resection of metastatic disease, when possible, is often considered optimal management of melanoma metastatic to the brain. Given the vast improvement in imaging techniques, beginning with the advent of CT scanning in the 1970s and MRI in the 1980s, the identification and selection of these patients has improved significantly. Several large surgical series have been published, and indicate that surgical resection has a definite beneficial role to play in carefully selected patients (TABLE 2). Sampson et al., from Duke University Medical Center (NC, USA), reported 702 patients with brain metastases in which they found a highly significant survival advantage in those who had resection (n = 139), compared with those treated with WBRT alone (8.2 vs 4.2 months; p < 0.001) [21]. Surgery had a salutary effect on symptoms in a large proportion of patients, with 50% of patients undergoing surgical resection reported to have improvements in neurologic symptoms, while 19% reported no change and the remainder worsened. However, there was substantial risk involved with surgery, with an 8.6% risk of death or life-threatening morbidity during the postoperative period [21].

n

Surgery

Study

Because of the relative ‘radioresistance’ of melanoma, many different fractionation schemes have been devised with larger doses per fraction to overcome the broad shoulder on cell survival curves of irradiated melanoma cells [17,27,28]. However, a review of several retrospective series reveals no fractionation schedule to be superior to the more standard fractionation schedule of 30 Gy in ten fractions, with the higher dose per fractionation schedules being more toxic [29–31]. There are no prospectively collected data regarding the benefit of using WBRT after surgical resection specifically in melanoma patients. One retrospective comparison of 35 patients undergoing resections of solitary metastasis showed lower brain metastasis-specific mortality in those treated with WBRT after surgery (24%) versus the untreated group (85%) [32]. A second retrospective series showed neither a decrease in CNS recurrence nor prolongation of survival [33] and another notes decreased risk of subsequent neurologic symptoms, but no effect on survival [21]. A randomized, multicenter trial by Patchell et al. compared surgery alone with the combination of surgery and postoperative WBRT in patients with brain metastases from a number of primaries. Recurrence anywhere in the brain was decreased (18 vs 70%; p ≤ 0.001) and recurrence was also decreased at the site of the original metastasis (10 vs 46%; p < 0.001) by the addition of WBRT to surgery [34]. Whether this applies to the radioresistant melanoma, however, is unclear. Nonetheless, based on the literature on this topic and the known benefits of WBRT in brain metastases patients, the use of WBRT after surgical resection could be considered standard.

Table 2. Series of surgical treatment of melanoma brain metastases.

Melanoma-induced brain metastases

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McWilliams, Rao, Buckner, Link, Markovic & Brown

Wronski et al. reported 91 patients surgically treated for their brain metastases over a period of 20 years at the Memorial Sloan-Kettering Cancer Center (NY, USA) [33]; the median survival of the patients was 8.5 months after initial diagnosis of brain metastases and 6.7 months after surgery. Out of a total of 91 patients, 76 had solitary metastases resected, and their survival was longer than those patients with multiple metastases resected (7.8 vs 5.4 months), though this difference was not statistically significant (p = 0.12). Overall, 47% of patients died of neurologic causes, including 15 (16%) of carcinomatous meningitis. Importantly, 40 patients (45%) had no recurrence of their brain metastases, with a median overall survival of 8.3 months [33]. Zacest et al., in a report from Royal Prince Alfred Hospital (Sydney, Australia), described 147 patients who underwent surgical resection of intracranial metastases [35]. Among these patients, gross total resection was accomplished in 85%, and only 27% died of intracranial disease. A total of five patients died within 30 days of surgery, including three from progression of brain metastases following subtotal resection. Similar to the Memorial Sloan-Kettering experience, almost half (66 or 45%) had no recurrence of brain metastases, and their median survival was 6 months. The main determinant of survival was the number of intracranial metastases, with those patients with one, two, or more than two sites having survivals of 8, 6, and 3.5 months, respectively. A total of 13 patients (ages ranging from 17–72 years old) survived at least 3 years after surgery for solitary metastasis. All of these long-term survivors had been treated with macroscopic total resections and postoperative WBRT [35]. Selection bias is always inherent in retrospective surgical series, which may affect differences in survival among surgical versus nonsurgical patients. A prospective trial comparing the role of surgery and other therapies in patients with brain metastases from melanoma is unlikely to be feasible in view of the ethical issues involved and patient aversion to being randomized to surgery, hence, retrospective reports will likely remain the basis of current practice. However, in the above series (and other series not discussed here) the presence of longterm survivors in patients with resected solitary metastases, and the decreased proportions of those dying from their brain metastases when compared with historical controls, argue in favor of performing surgical resection when indicated and feasible [29,36,37]. This conclusion is bolstered by the findings of two prospective randomized trials (in which only a minority of patients had melanoma) of patients with solitary brain metastases, which found that surgical resection combined with postoperative WBRT resulted in a significantly longer survival compared with WBRT alone for highly selected patients [38,39]. Apart from improving survival, surgically treated patients have been reported to have improved neurological function [40,41]. In summary, surgical resection of solitary metastases of melanoma in the brain, when possible, has a role in obtaining local control [33,35], and potentially improving neurological

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function. While SRS (discussed later) may present a less invasive option for some of these patients, candidates for surgical resection should be carefully selected, for example, to include those with large, dominant lesions, or lesions causing severe symptoms, such as hydrocephalus or refractory seizures, that are not amenable to other therapeutic interventions. The status of systemic disease should also be weighed against the risks and expected recovery time of surgery. There are no prospective data supporting the use of surgery in those with multiple brain metastases. Stereotactic radiosurgery

SRS (e.g., gamma knife, linear-accelerated-based radiosurgery, charged particles, and CyberKnife®) involves the delivery of a large, single-fraction of radiation to a stereotactically localized intracranial volume. In contrast to conventional fractionated radiation therapy, radiosurgery does not rely on fractionation (i.e., multiple small daily doses) and the increased radiation sensitivity of the target compared with the normal brain to achieve a beneficial therapeutic ratio. Rather, SRS spares normal structures by physical deposition of significant doses of radiation into the target lesion with steep fall-off of dose at the edges of the target; this is commonly achieved by the use of many radiation fields distributed over space all focusing on a target. The advantages of SRS include the ease of use (single-day therapy), ability to treat patients who are not surgical candidates (due to location or comorbid conditions), and decreased neurosurgical morbidity. Since most brain metastases are small, spherical and have distinct margins, they are ideal targets for SRS, which minimizes the amount of radiation delivered to nontarget areas of the brain. This technique is being increasingly utilized in the management of unresectable solitary or oligometastatic disease in the brain in patients with stable or absent systemic disease and good performance status. Although there is not a hard and fast rule for an upper limit on the number of metastases or size of metastases that can be treated with SRS, many consider a patient presenting with four or fewer metastases and all lesions smaller than 4 cm, a reasonable candidate for SRS. However, it is important to emphasize that there are many variables that enter into these decisions (e.g., location of metastases, performance status of patient, systemic-disease status of patient, and so on) and a nuanced discussion of all these variables and their impact on treatment decisions is beyond the scope of this review. Although SRS may be an attractive alternative to surgery, the question often arises as to which modality is better, surgery or SRS, in the treatment of brain metastases. Retrospective comparisons between these modalities have conflicting results and are inherently flawed due to a number of selection biases, owing to the fact that SRS and neurosurgery are applicable to different and somewhat nonoverlapping patient populations [42,43]. Currently, there is only one small prospective trial (having only been reported in abstract form) that randomized 64 patients with a

Expert Rev. Anticancer Ther. 8(5), (2008)

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[98]

86.2 1 54 40.5 5.3 Clinical trial. NR: Not reported; WBRT: Whole-brain radiotherapy.

*

244

3.1 (2–14) 40 Mathieu (2007)

NR

29

3.5 (1–10) 50 Samlowski (2007) 44

45

[56]

NR 18 53 48 9.4

NR NR 58 14 Manon (2005)*

0

8.3 (all histologies) 38

8.9 31 Fife (2004)

3.7 (1–18) 51 Radbill (2004)

48

[55]

68 (at 6 months)

[46]

[54]

81 32 53 NR 6.0 20

[53]

49 (75% for tumors < 2cm) 19 51 45.6 6.0 59

1.5 (1–4) 103 Selek (2003)

55

[52]

82 NR 53 18 10.4 51

2.0 (1–7) 45 Mingione (2002)

36

[51]

91 5 58 37 9.7 NR

2.0 (1–9) 23 Brown (2002)

48

[50]

97 NR 53 8 8.0 40

2.1 (1–5) 45 Lavine (1999)

NR

[49]

88 6 57 43 7.0 49

1.6 (1–5) 35 Grob (1998)

0

[48]

90 5 49 15 7.0 60

2.0 (1–12) 60 Mori (1998)

85

[97]

77 2 52 35 8.1 32

83

2.4 (1–6) 40 Seung (1996)

52

[45]

97 9 46 5 7.0 100 23 Somaza (1993)

1.4 (1–4)

Patients n with solitary Mean (n) metastases (%) number of metastases (range)

n Median survival receiving after treatment WBRT (%) (months)

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Surgical series

Table 3. Radiosurgery series for melanoma brain metastases.

single metastasis (maximum diameter 3 cm) to either radiosurgery alone or microsurgery followed by WBRT [44]. There was no significant difference in the overall length of survival, mortality due to neurological complications, or local tumor control (although there was a trend in favor of SRS: 97 vs 82%; p = 0.06). SRS was associated with an improved quality of life 6 weeks after treatment. As might be expected, patients treated with SRS (since they did not receive adjuvant WBRT) had a higher rate of distant brain failure, and required salvage therapy more frequently. Due to the small patient numbers in this study, these results need to be interpreted with caution. With the reviewed limitations, the literature on this topic suggests that local control rates are equivalent between those treated with SRS and surgery. The currently available data also suggest that SRS is more convenient, effective and safer, for smaller lesions, for patients with two or more lesions, and for lesions in inaccessible locations, and also for patients who are not surgical candidates for medical reasons. On the other hand, surgery is clearly the optimal modality for lesions causing a mass effect. In summary, SRS and surgical resection should be seen as complementary, but different, modalities to be utilized in the treatment of select patients with brain metastases [45]. In carefully selected patients, local control rates of over 90% have been reported. Studies to date are summarized in TABLE 3. The first series published by Somaza et al. in 1993 reported 23 patients with lesions less than 3 cm in diameter (19 with solitary metastases, four with multiple lesions) who underwent radiosurgery in addition to external-beam WBRT (30 Gy/10 fractions). Overall, 19 died of systemic disease (rather than CNS disease), one of intracerebral hemorrhage, and there were only two (9%) intracranial recurrences. Morbidity of the procedure was low, as only one patient required craniotomy for hemorrhage into a tumor bed. Median survival was 9 months [46]. Subsequent series have shown comparable results with regard to local control rates (80–90%, with a trend over time toward an increasing number of lesions treated (TABLE 3).

Deaths from Median Subsequent Local control rate Ref. brain age surgery (%) at 1 year (or last metastases (%) (years) reported) (%)


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Perhaps correspondingly, the proportion of patients dying as a result of their brain metastases has also appeared to increase, likely reflecting the higher-risk patients with multiple lesions in the brain [47–57]. Retrospective series are limited, owing, in part, to incomplete imaging follow-up. Many patients are only imaged if they have recurrent or worsening symptoms, and the median survival of 6–10 months precludes adequate long-term follow-up data. In a prospective study performed with scheduled follow-up (E6397), 31 SRS-treated (without WBRT) patients with melanoma (45%), renal cell carcinoma (45%), or sarcoma (10%) had local control rates within the treated area of 68% at 6 months [56]. Overall intracranial failure was 48.3% at 6 months, higher than had been reported in retrospective series; the authors noted the poor results achieved in this study were most likely due to the lack of adjuvant WBRT and the “routine avoidance of WBRT should be approached judiciously”. Unfortunately, the small number of melanoma patients in this study, and the lack of melanoma-specific information reported somewhat limit the utility of this study. In the RTOG 9508 trial randomizing 333 patients with one- to three brain metastases of any histology to WBRT with or with SRS boost, no survival difference was observed overall. However, in subset analysis, an increased survival was noted for the SRS arm for those with solitary metastases (6.5 vs 4.9 months; p = 0.039), and the SRS arm had a higher KPS at 6 months follow-up. However, these findings were not the primary end point of the study and, therefore, require confirmation in other studies. In addition, only seven melanoma patients were included in each arm [58]. The relationship between the size of the lesion and rate of local control continues to be debated. One small study of 12 patients suggested that efficacy was compromised with lesions over 1.0 cm [59], but subsequent series have noted no such observation, with local control rates over 90% despite the lesions preserve of up to 3.5 cm [49,51,52,60]. Stabilization or improvement in focal neurologic symptoms has been noted in 78–100% of treated patients [49,51]. In one recent series, 18% of lesions progressed locally, although six patients of a total of 45 who had solitary metastases in the brain and no visceral disease were alive at the end of the study, with survival ranging from 14–82 months [53]. WBRT is commonly given after SRS. Its use is controversial, as it appears to prevent the formation of new lesions, but has not been shown to improve survival or decrease death from neurologic causes [49,53–55,61]. A retrospective review of 100 consecutive patients (21% melanoma) treated with SRS alone found a 1-year actuarial risk of distant brain failure of 61% for all patients. Significant predictors of distant brain failure on univariate and multivariate analyses were the presence of greater than three metastases (hazard ratio [HR]: 3.30, p = 0.004), stable or poorly controlled extracranial disease (HR: 2.16; p = 0.04), and melanoma histology (HR: 2.14; p = 0.02). Actuarial freedom from distant brain failure at 1 year was 27.6% for melanoma

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versus 40% all other histologies (p = 0.02). The authors noted these high-risk factors could be utilized to select higher-risk patients for adjuvant WBRT after SRS [62]. A Japanese multicenter Phase III trial of SRS with or without WBRT (30 Gy, ten fractions) has been reported, with 132 patients with one to four brain metastases of any histology. Actuarial 1-year survival in the combination arm was 39 versus 28% in the SRS-alone arm. (p = 0.42). Local control rates were 70% for SRS alone and 88% for SRS plus WBRT (p = 0.019). The 12-month actuarial brain tumor recurrence rate was 46.8% in the WBRT plus SRS group and 76.4% in the SRSalone group (p < 0.001). The actuarial local tumor control rate at 12 months was 88.7% in the WBRT plus SRS group and 72.5% in the SRS-alone group (p = 0.002) [61]. In summary, the use of SRS alone has the advantage of avoiding the cost, time, and toxicity of WBRT. The disadvantage is that patients may have a higher risk for local and distant CNS relapse. Indeed, at least one study has found the majority of recurrences in the brain to be symptomatic and associated with a neurologic deficit [63]. Proponents of SRS alone argue that CNS relapses can be salvaged with subsequent SRS or surgery. However, in order to do so, patients would need to be followed closely with exams and imaging and, in a certain proportion of patients, the lesions may not be amenable to any form of subsequent therapy. An ongoing North Central Cancer Treatment Group (NCCTG N0574) study (with a number of neurocognitive and quality of life measures) is randomizing patients with one to three brain metastases to SRS alone, or SRS plus WBRT, and will better elucidate the role of adjuvant WBRT in patients treated with SRS. No study has yet reported superiority of one type of SRS over another. Overall, local control with SRS is excellent, and it is less invasive than craniotomy. Long-term survival has been demonstrated in the minority of patients who have brain-only metastases, and it is relatively well tolerated, though salvage surgery for late-symptomatic hemorrhage or recurrence is not infrequently required. Chemotherapy

Given the poor overall response rate (RR) to chemotherapy in melanoma metastatic to extracerebral sites [64], it is not surprising that chemotherapy alone has been largely unsuccessful in treating brain metastases. One prospective study of patients with brain metastases from various primary tumor types treated with cisplatin and etoposide noted a complete lack of responses in melanoma patients, compared with a 39% RR in patients with brain metastases from breast cancer and a 30% RR in non-small-cell lung cancer [65]. Carmustine, a nitrosourea with modest activity against extraCNS melanoma [66], has also been used with little success in melanoma metastatic to the brain [24], despite theoretical penetration of the blood–brain barrier (BBB) [67]. Subsequently, attempts have been undertaken to identify more active agents



that cross into the CNS in adequate quantities to have an antitumor effect. Fotemustine, a nitrosourea with high CNS penetration, was an early candidate. Phase II European studies initially reported RRs of brain lesions from 12–25% in abstract form [68,69], though RRs dropped from 12 to 5% in one study as the eligibility criteria were loosened to make the drug more available to the population [68]. Fotemustine is currently unavailable in the USA. Temozolomide (TMZ), a dacarbazine analogue with high CNS penetration, has been approved by the US FDA for use in patients with primary brain tumors. Enthusiasm for study of TMZ in brain metastases from melanoma increased when a complete response of multiple brain metastases from melanoma after six cycles of TMZ was reported in 2001 [70]. Interestingly, the patient had had a complete response outside the CNS to a combination of dacarbazine, IFN-α, and cisplatin 2 months previously, but had relapsed only in the brain, perhaps illustrating the superior CNS penetration of TMZ, and also, perhaps, an unusual sensitivity of this patient’s melanoma to chemotherapy. Nonetheless, the role of chemotherapy is still limited in melanoma, with TMZ producing a RR in extra-CNS melanoma of 12–20% [71,72]. In a retrospective series of TMZ-based chemotherapy for brain metastases from melanoma, Bafaloukas et al. reported a 24% overall partial RR in 25 patients (six monotherapy, ten with docetaxel, nine with cisplatin), with a 17% RR treated with TMZ monotherapy. Responding patients had improved neurologic status and performance score, and decreased steroid use from baseline. The primary toxicities were hematologic [73]. Agarwala et al. reported a multicenter Phase II study of 151 patients with brain metastases from melanoma [74], with a TMZ treatment schedule of 200 mg/m2, using a 5-day regimen repeated every 28 days (150 mg/m2 for previously treated patients). Concurrent or prior radiation therapy was not permitted. Overall, 6% of patients responded in the brain, with 26% having stable disease for 8 weeks. Median survival was 3.5 months. Toxicity was modest, with less than 10% grade 3 or 4 toxicity in any category. Because of the vascular nature of melanoma, the combination of thalidomide, an antiangiogenesis agent, and TMZ is being explored in patients with brain metastases from melanoma. A Phase II study of 38 patients in extra-CNS metastatic melanoma showed a RR of 32% [75]. One complete response in a patient with multiple brain metastases and leptomeningeal disease was reported out of a series of 16 patients with melanoma brain metastases treated at Memorial Sloan-Kettering [76]. In a Phase II study from the same group, 26 patients with multiple brain metastases were treated with a 6 out of 8-week daily dose of TMZ at 75mg/m2 daily and daily thalidomide (200–400 mg). A RR of 12% was observed, with a median survival of 5 months reported. Notably, seven patients (27%) were reported to have a grade 4 CNS hemorrhage, and three (12%) were reported to have a grade 4 thromboembolism.


Review

A second, multicenter trial through the Cancer and Leukemia Group B (CALGB 500102) using the same schedule enrolled 16 patients, but ceased accrual after noting an excess of thromboembolic events (25%) and one sudden death, all in the first cycle, and no clinical responses. Excess thromboses are well known to occur in other malignancies when thalidomide is used [77]. Overall, given the significant toxicity and relative lack of efficacy of thalidomide noted in systemic therapy trials, the drug does not currently appear to have a role in the treatment of melanoma-induced brain metastases. However, the successful clinical use of bevacizumab (an antibody targeting VEGF A) in glioblastoma multiforme patients is of interest [78]. Though thromboses are observed, the apparent efficacy in progression-free survival may allow use of this or similar antiangiogenic agents in the setting of brain metastases. If preliminary evidence of activity of bevacizumab-containing regimens in melanoma is confirmed [79], these could potentially be studied in patients with brain metastases. Though our limited clinical experience with patients in this setting has not shown significant clinical hemorrhages, a frank discussion with the patients about the risks of brain hemorrhage and thrombosis risk would be paramount. Combination therapy: chemotherapy & external-beam radiation

Owing to potential improved benefits, the combination of chemotherapy with external-beam radiation is being actively explored. A European study first evaluated the role of fotemustine (100 mg/m2 days 1, 8, 15) in patients with brain metastases with or without whole brain irradiation (37.5 Gy over 15 fractions. The RR (7.4% fotemustine alone vs 10% fotemustine plus WBRT) and survival (86 vs 105 days) were slightly higher in the combination therapy arm, although the difference was not statistically significant [80]. Two Phase II trials have been reported using concomitant TMZ and radiation therapy, followed by TMZ alone. In the first study, 20 patients were treated with daily TMZ (60 mg/m2/day), and given ten 300 cGy fractions of WBRT with a 6–9 cGy boost, followed by standard dose TMZ 200 mg/m2 × 5 days monthly × 6 after radiation. The RR was 55%, with a brain tumor control rate (RR plus stable disease) of 85% at 3 months. At 8 months, 14 patients were alive and only one grade 3 toxicity (thrombocytopenia) was noted. No toxic deaths were noted [81]. A multicenter US trial of 31 patients used a daily dose of TMZ of 75 mg/m2 for 6 out of 10 weeks, starting with the commencement of radiation and WBRT with a dose of 300 cGy for ten fractions without a boost [82]. This was followed by the same schedule of TMZ repeated every 10 weeks instead of the 5-day monthly regimen. The RR was lower (only 10%) and median survival was 6 months, with a median progression-free survival of 2 months. One patient died of neutropenic sepsis, but the treatment was otherwise well tolerated. The reason for the disparity in these

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two studies is unclear, and may be due to small sample size and statistical variation. However, the addition of boost treatment to tumor sites, and the differing schedule of TMZ may account for the differences. Atkins et al. reported 40 patients treated in a Phase II trial of TMZ/thalidomide combined with WBRT (30 Gy/10 fractions) for melanoma-induced brain metastases. The intracranial RR was 7.7% with no systemic responses. The neurotoxicity rate (grade 3 adverse events or higher) was 20%, and 45% required hospitalization for side effects or progression [83]. At this time, as noted above, it is unlikely that further evaluation of a thalidomide/TMZ combination is warranted. The combined modality approach, overall, will require identification of more effective systemic therapies for melanoma in order to substantially reduce morbidity and mortality from melanoma metastatic to the brain. Even if an agent is effective in increasing radiosensitization, rapid systemic progression is a substantial possibility in the absence of systemically effective therapy against melanoma. One noncytotoxic agent, efaproxiral (RSR13), an allosteric modifier of hemoglobin intended to enhance tumor oxygenation and subsequently augment radiation-induced oxidative damage, showed promise in early trials of brain metastases [84]. However, in a large Phase III trial including 515 patients with brain metastases of solid tumors (excluding germ cell and small-cell lung cancer), there was a reduction in the risk of death in the efaproxiral arm (HR: 0.87), but this did not reach statistical significance. The benefit appeared to be mostly among breast cancer patients [85]. The number of many melanoma patients that may have been included and their results was not reported. Immunotherapy

Immunotherapy alone for brain metastases from melanoma is plagued with the same challenges as chemotherapy alone; uncertainty regarding drug delivery and efficacy in the CNS. The tolerability of high-dose IL-2 in melanoma patients with brain metastases was demonstrated in a retrospective study by the National Cancer Institute (MD, USA), and some efficacy was noted (5.6% RR), but those with brain metastases had a lower overall RR than those without [86]. Though there have been case reports of dramatic responses to immunotherapy alone [87] and in combination with chemotherapy [88], patients with brain metastases have increased survival when their metastases are definitively treated with SRS or surgery [89]. For now, if systemic immunotherapy is considered, additional attempts at definitive locoregional treatment of intracranial disease is prudent. Two antibodies targeting CTLA4, an inhibitory feedback signal expressed by activated T cells, are in Phase III trials after demonstrating some activity in advanced melanoma. As might be expected for immunotherapies, ipilumumab and tremelimumab have both shown a modest number of impressive complete and partial responses [90], and there is a tendency for improved

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survival compared with historical controls [91]. Toxicity has largely been autoimmune, with bowel inflammation among the most notable sequelae [92]. Expert commentary

Brain metastases are a life-threatening and morbid complication of metastatic melanoma. Their rapid progression and predisposition to hemorrhage make management imperative, yet problematic; cessation of their progression is key to improving survival and quality of life. The paucity of prospective, randomized trials regarding brain metastases from melanoma makes firm recommendations for management of patients afflicted with this diagnosis difficult. A potential algorithm outlining management recommendations is provided in FIGURE 1. In the setting of a symptomatic solitary metastasis, surgery is likely to be of some benefit. However, the utility of this modality is lower in those with multiple metastases. Lacking clear data to fully characterize the total number of lesions surgically resectable, in our opinion, a reasonable cutoff is three lesions, and this is only true if they are accessible through a maximum of two craniotomy sites. SRS for solitary lesions less than 3–3.5 cm in diameter without significant mass-effect symptoms is an excellent alternative to surgery due to its low morbidity, and surgery may still be available if symptoms progress. Radiosurgery may also play a role in patients with oligometastatic disease, unresectable lesions, or in those patients too ill for craniotomy. Certainly in patients with a good performance status and a reasonably small number of lesions, consultation with a physician experienced in radiosurgery and microsurgery should be considered; however, it is important that SRS (and surgical resection) in general be reserved for highly selected patients since the expected benefit of SRS (or surgical resection) for patients with progressive systemic disease and/or poor performance status will be small. For patients with several lesions that are primarily symptomatic from one dominant tumor, surgical excision of the latter with radiosurgery for the remainder would be a reasonable approach. The primary focus of all management decisions should revolve around reasonable management goals given the clinical situation for a particular melanoma patient, including systemic burden of disease, rate of progression, and performance status. If systemic disease is widespread and progressive, then, clearly, less invasive treatments such as WBRT or, simply, supportive care are indicated. If, however, systemic disease is under good control in a reasonably healthy patient, aggressive surgical/radiosurgical interventions may be more appropriate if feasible and available. Good clinical judgment should always supersede blanket treatment recommendations. For those patients who have had local therapies (i.e., radiosurgery or resection) for brain metastases, performing periodic MRI scans at 2–3 month intervals is a reasonable approach, as these patients are at risk for development of subsequent metastases, and subsequent treatment with surgery, radiosurgery, or



Review

Systemic disease status/performance status

Stable or absent systemic disease/ good performance status

Progressive systemic disease/ poor performance status

Number of metastsases

Solitary/dominant lesion

Is there significant mass effect? Is the lesion resectable? Yes Surgery

Adjuvant WBRT

Small number of lesions

If lesions are suitable for radiosurgery or radiosurgey/surgery combination: follow pathway for solitary metastases

Large number of lesions

If not suitable for local therapy: follow pathway for multiple lesions

Consider clinical trial chemotherapy/WBRT

No Sterotactic radiosurgery (gamma knife or linear accelerator)

No WBRT

Adjuvant WBRT

If not on study: WBRT (30 Gy, 10 function) ± systemic therapy if disease outside CNS

No WBRT

Figure 1. Clinical management of brain metastases from melanoma. WBRT: Whole-brain radiation therapy.

WBRT are often feasible strategies. Radiosurgery or surgery can potentially be repeated in new sites, or the other can be used on a given lesion if the initial treatment fails. WBRT can be utilized as a either a palliative salvage therapy on progression if not used as an adjuvant treatment to local therapy. As opposed to patients with primary brain malignancies, the distinction between radiation necrosis and tumor is less critical, since systemic therapies are unlikely to be discarded on the basis of progression of brain metastases. For patients who encounter new neurologic symptoms from previously treated lesions, SRS or surgery can be considered in addition to supportive measures such as steroids or antiepileptics as the situation may warrant. The utilization of WBRT on those with lesions or clinical situations not amenable to local therapies is appropriate, as improvement in quality of life for some patients has been demonstrated. However, the modest RR and limited effect on survival suggest a clear need for improvement. The role for adjuvant WBRT after surgery and radiosurgery is not proven, though often used to prevent recurrence and decrease the possibility of new metastases elsewhere in the brain. In this setting, consideration must be given to the chance of radiation-induced dementia [93], given the possibility, albeit small, of long-term survival after successful treatment of brain metastases [21,33,35]. For now, the decision to use WBRT in the adjuvant setting must weigh up the possibility of decreasing the risk of recurrence with the risk of long-term complications, and a discussion of these factors between the clinician and patient is mandatory.


Two ongoing studies by the NCCTG (N0574) and the European Organization for Research and Treatment of Cancer (EORTC 22952) are attempting to answer the role of adjuvant external-beam radiotherapy after radiosurgery (or surgery in the case of the EORTC trial). Chemotherapy, specifically TMZ, may play a role in augmenting the benefit of WBRT, and combined modality approaches appear to be promising avenues for investigation in the future. However, to date, data have not demonstrated a benefit to this approach. Prospective, randomized trials in this disease would provide the best guidance for management, but in their absence, RPA stratification may provide the most helpful means of comparison between groups with differing interventions. Future series would be most helpful if these analyses were included, and prospective trials should include this stratification as well. The need for improvement in our management of these patients is evident in their poor survival, and an evidence-based approach is a sine qua non to this end. An additional consideration, given the high rate of brain metastases from melanoma, is the issue of screening for metastatic disease in the CNS. Outside of stage IV disease, there does not appear to be any role for routine screening [94]. In the large series by Sampson et al., 702 patients with brain metastasis were identified, of which 118 had a solitary lesion, and 139 underwent surgery (19.8%) Surely, this also reflects a referral bias, with patients with surgically treatable disease more likely to be referred to a surgical center. However, the treatment of increasing

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numbers of lesions with SRS may increase the percentage of patients with disease amenable to intervention. A populationbased study of the true incidence of instrumentable disease is required to definitively answer the question. Subsequently, a prospective study comparing screening versus no screening would be required to definitively answer whether screening would improve outcome and survival. Five-year view

Predicting the future with regard to melanoma treatment is at best, difficult given the lack of significant antitumor activity of any systemic agent. However, given the explosion of novel therapeutics in the treatment of human cancer, there is no doubt there will be a role for them in melanoma. Chemotherapy combinations utilizing taxanes and platinum agents appear to provide somewhat longer disease control than previously reported regimens [95,96]. In addition, given the very vascular nature of these tumors, antiangiogenic therapy is a strong area of interest in melanoma, with trials underway utilizing small molecule and antibody inhibitors of relevant novel targets. Currently, many trials are largely excluding patients with brain metastases, due to a theoretical risk of intracranial hemorrhage. It is very possible that one or several of these agents will prove effective in systemic therapy in melanoma. If this occurs, we will likely see testing in patients with brain metastases as well.

Other small molecule agents that affect growth factor signaling, apoptosis, and cell-cycle pathways will no doubt also be studied as well, and may lead to further investigation into combined modality therapy trials. Other agents that cross the BBB intended to disrupt the vasculature are also in development. Clearly, the development of effective systemic therapy for melanoma will also aid in treatment of brain metastases. In addition, the increasing role of SRS should be further defined. The limits of SRS treatment with regard to number and size of lesions amenable to treatment may begin to answered. If systemic progression can be curtailed to a larger extent, more aggressive treatment regimens utilizing SRS and other modalities may be increasingly justifiable, perhaps leading to additional screening as well. In 5 years, the morbidity and mortality of brain metastases from melanoma may not be significantly changed, but the picture should become clear as to the future direction of study. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript.

Key issues • Brain metastases from melanoma are common, and confer a poor prognosis, with median survival below 4 months. • Prognostic indices can stratify prognosis based on clinical criteria, and may aid in comparison of studies. • Surgical series suggest a benefit from removal of solitary metastasis, with a potential for long-term local control. • Stereotactic radiosurgery (SRS) is an increasingly utilized technique with promising local control rates. SRS can be used in cases with more lesions than with surgery and SRS is also less invasive. • External-beam radiation therapy has a role in palliation of patients with multiple metastases, and may reduce new sites of CNS metastases in those treated locally with surgery or SRS, though no proven survival benefit has been shown. • To date, chemotherapy and immunotherapy alone are not active in brain metastases resulting from melanoma. • Chemotherapy combined with external-beam radiation therapy is under investigation, but will require more active systemic agents to realize its promise. • Future directions include novel agents such as antiangiogenesis agents. 3

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Affiliations •

Robert R McWilliams, MD Division of Medical Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Tel.: +1 507 284 8432 Fax: +1 507 284 1803 [email protected]

•

Ravi D Rao, MD Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Tel.: +1 507 284 2511

•

Jan C Buckner, MD Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Tel.: +1 507 284 2511

•

Michael J Link, MD Department of Neurosurgery, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Tel.: +1 507 284 2511

•

Svetomir Markovic, MD, PhD Department of Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Tel.: +1 507 284 2511

•

Paul D Brown, MD Department of Radiation Oncology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Tel.: +1 507 284 2511

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