melanoma

Temozolomide in Advanced Malignant MelanomaWith Small Brain MetastasesCan we Withhold Cranial Irradiation?

Willem Boogerd, MD, PhD1

Gijsbert C. de Gast, MD, PhD2

Otilia Dalesio, MSc3

1 Department of Neuro-oncology, NetherlandsCancer Institute, Amsterdam, Netherlands.

2 Department of Medical Oncology, NetherlandsCancer Institute, Amsterdam, Netherlands.

3 Department of Biometrics, Netherlands CancerInstitute, Amsterdam, Netherlands.

BACKGROUND. The efficacy of radiotherapy (RT) in patients who have brain me-

tastases from melanoma is limited. In this study, the authors evaluated the effi-

cacy of treatment with temozolomide in patients with metastatic melanoma,

including small brain metastases, who did not require immediate RT and investi-

gated the feasibility of deferring RT.

METHODS. Patients with brain metastasis were identified from 3 prospective stu-

dies of temozolomide (with or without immunotherapy) for metastatic mela-

noma. Patients with brain metastasis that measured >2 cm, extensive edema,

and localization in the brain stem were excluded from the study. For the current

analysis, patients with leptomeningeal metastasis and patients who received pre-

vious stereotactic RT were excluded. In patients who achieved a systemic re-

sponse or stabilization to temozolomide, the response of brain metastasis and

the necessity for palliative cranial RT were evaluated.

RESULTS. Among 179 patients who received temozolomide for advanced mela-

noma, 52 patients with brain metastasis were evaluable. Stabilization of systemic

metastasis was noted in 7 of 52 patients (13%), and there were 6 responses (5

partial responses and 1 complete response; 11%); thus, in those 13 patients, 6

had stabilization of brain metastasis (11%) and 5 had a response (2 partial

responses and 3 complete responses; 9%). Immunotherapy did not influence the

neurologic response. The median time to neurologic progression was 7 months

(range 2–15, months). RT for cerebral recurrence was required in 2 patients. The

median survival of patients with brain metastases was 5.6 months (95% confi-

dence interval, 4.4–6.8 months). Intracranial hemorrhagic complications were not

observed.

CONCLUSIONS. The current results indicated that it is feasible to treat patients

who have advanced melanoma and small brain metastasis with temozolomide as

the single treatment. The small subset of patients with systemic response usually

showed durable stabilization or a response of brain metastasis. With this approach,

neurologic disease can be controlled, and cranial irradiation may be deferred and

even withheld in most of patients. Cancer 2007;109:306–12.

� 2006 American Cancer Society.

KEYWORDS: melanoma, brain metastasis, temozolomide, radiotherapy.

M elanoma has a high propensity to metastasize to the brain

with reported incidence from �10% in clinical series to >50%

established by autopsy.1–3 Usually, brain metastases occur late in the

course of metastatic disease with wide-spread extracranial metasta-

ses. Metastases of melanoma in visceral sites and in the brain have

the worst prognosis. Occasionally, patients with brain metastasis

can be treated effectively with surgery or stereotactic radiotherapy

Supported by a grant from A research grant fromSchering-Plough Corporation, Maarssen, theNetherlands.

Address for reprints: Willem Boogerd, MD, PhD,Department of Neuro-oncology, Netherlands CancerInstitute, Plesmanlaan 121, 1066 CX Amsterdam,Netherlands; Fax: (011) 31 20-5122572; E-mail:[email protected]

Received June 1, 2006; revision receivedOctober 12, 2006; accepted October 23, 2006.

ª 2006 American Cancer SocietyDOI 10.1002/cncr.22411Published online 5 December 2006 in Wiley InterScience (www.interscience.wiley.com).

306

(RT) when they are confined to �3 small lesions and

when there is no extracranial disease activity.4–6 The

standard treatment for patients with symptomatic

brain metastasis and active extracranial metastases

consists of whole-brain RT (WBRT) in combination

with corticosteroids that, nonetheless, is barely effec-

tive (the median survival is about �3, and most trea-

ted patients dye of neurologic disease).1,2,7–9 In fact,

the objective response rate of symptomatic brain

metastasis from melanoma to conventional WBRT

probably is not greater than 15%7,10; and, for the ma-

jority of patients, the burden of such treatment may

have more negative impact on the quality of life than

the doubtful benefit to survival compared with corti-

costeroids and other supportive measures. Data

about the efficacy of RT in patients with asymptom-

atic brain metastasis from melanoma are lacking.

The standard treatment for patients with meta-

static melanoma is dacarbazine, which produces sys-

temic response rates from 10% to 15% and produces

somewhat lower response rates in visceral sites.11,12

A randomized trial comparing temozolomide with

dacarbazine in patients with metastatic melanoma

showed equivalent response rates and survival.11

Temozolomide is an analogue of dacarbazine that

has excellent oral bioavailability and relatively high

central nervous system (CNS) penetration. A large

Phase II study of temozolomide for patients with

brain metastasis from melanoma13 who did not

require immediate RT showed that temozolomide

was tolerated well and produced an overall objective

response rate of 6% and a stable disease (SD) rate of

26%, which is comparable to the response in patients

with visceral extracranial metastasis. In the current

study, we assessed the response of brain metastasis

in patients who showed a response to temozolomide

of systemic metastatic disease, and we evaluated

whether it is feasible to defer or possibly withhold

cranial RT.

MATERIALS AND METHODSThe group of patients for this report consisted of

patients with metastatic melanoma from 3 consecu-

tive prospective studies: 1) a Phase II study with

escalating doses of temozolomide (150–250 mg/m2)

for 5 days followed by immunotherapy with subcuta-

neous granulocyte-macrophage–colony stimulating

factor (GM-CSF) (2.5 mg/kg), subcutaneous low-dose

interleukin 2 (IL-2) (4 MIU/m2), and subcutaneous

interferon a (IFNa) (5 MIU fixed dose) for 12 days

every 4 weeks, as described previously14; 2) a Phase

III study with temozolomide 200 mg/m2 for 5 days

every 4 weeks with or without immunotherapy as

described above; and 3) a Phase II study with temo-

zolomide 200 mg/m2 for 5 days every 4 weeks.

Eligibility criteria for the 3 studies were histologi-

cally proven melanoma with extracranial metastatic

disease, age >18 years, a Karnofsky performance status

�70, adequate bone marrow function (leukocytes,

�4.0 � 109/L; platelets, >100 � 109/L), adequate re-

nal function (creatinine, <180 mmol/L), and adequate

liver function (transaminase and alkaline phosphatase

levels, <3 times the upper limit of normal [ULN]; in

patients with liver metastases, <5 times the ULN; bili-

rubin, within normal limits). No previous chemother-

apy or immunotherapy except adjuvant IFNa was

allowed. All patients had gadolinium-enhanced mag-

netic resonance imaging (MRI) brain scans as a

screening procedure before the start of treatment.

Patients who had brain metastases that measured >2

cm in greatest dimension, localization in the brain

stem, and edema that required steroid treatment were

excluded. Whether edema required steroid treatment

was determined by an experienced neurologist (W.B.)

and was based on neurologic and radiologic findings.

From the total of 179 patients who were included in

the 3 prospective studies, 57 patients also had evi-

dence of CNS metastasis. For the current study of pa-

tients with brain metastases, previous stereotactic RT

(n ¼ 1 patient) and leptomeningeal metastasis (n ¼ 4

patients) were excluded.

Evaluation of ResponseRadiologic studies of all involved sites were obtained

at baseline and after every even-numbered treatment

cycle. Responses of both intracranial and extracranial

sites were defined according to the following criteria:

a complete response (CR) was defined as the com-

plete disappearance of tumor, a partial response (PR)

was defined as a decrease �50% in the product of

the 2 greatest perpendicular tumor dimensions, SD

was defined as a decrease <50% or an increase

<25% in the product of the greatest perpendicular

tumor dimensions, and progressive disease (PD) was

defined as an increase >25% in the product of the

greatest perpendicular tumor dimensions or the

appearance of new lesions.

Responses in intracranial sites and extracranial

sites were recorded separately. In patients who were

diagnosed with overt clinical and radiologic extracra-

nial PD that resulted in the decision to stop further

chemotherapy (n ¼ 40 patients), MRI brain scans

were not obtained routinely. Therefore, for the cur-

rent study, the evaluation of response of brain metas-

tases was restricted to patients who had disease

stabilization or patients who had a response of extra-

cranial metastatic disease (n ¼ 13 patients).

Temozolomide in Small Brain Metastases/Boogerd et al. 307

Statistical AnalysisSurvival was calculated from the start of treatment

until death. Survival curves were constructed by

using the Kaplan Meier method. Comparison of the

curves between the groups was done by using the

log-rank test.

RESULTSEighty-one patients were included in the Phase II

study of escalating-dose temozolomide with immu-

notherapy for metastatic melanoma, 79 patients were

enrolled in the randomized Phase III study of temo-

zolomide with or without immunotherapy, and 19

patients were included in the Phase II study of temo-

zolomide alone. The characteristics of the patients

are listed in Table 1. The majority of patients (68%)

had visceral metastases. The characteristics of the 52

evaluable patients who had brain metastases are

listed in Table 2. Among these patients (23 patients

who received temozolomide with immunotherapy

and 29 patients who received temozolomide without

immunotherapy), 6 patients (11%) showed a response

of extracranial metastatic melanoma (5 PRs and 1 CR;

2 patients after temozolomide and immunotherapy

and 4 patients after temozolomide alone), and 7 pa-

tients (13%) had stabilization of extracranial metastatic

melanoma (4 patients after temozolomide and immu-

notherapy and 3 patients after temozolomide alone),

accounting for 25% response or stabilization. Among

these 13 patients, 5 patients (9%) showed a response of

brain metastasis (2 PRs and 3 CRs; 2 patients after

temozolomide and immunotherapy and 3 patients

after temozolomide alone), and 6 patients (11%) had

stabilization of brain metastasis (4 patients after temo-

zolomide and immunotherapy and 2 patients after

temozolomide alone), accounting for 21% response or

stabilization (Table 3). The disease characteristics of

these 11 patients (Table 4) did not differ significantly

from the nonresponders. Eight of 11 responders had

TABLE 1Patient Characteristics (N 5 179)

Characteristic No. of patients (%)

Men 113 (63)

Women 66 (37)

Median age [range], y 49 [20–75]

Site of metastasis

Skin, soft tissue, lung (M1a,b) 58 (32)

Visceral (M1c) 121 (68)

CNS 57 (32)

Brain metastasis 53

Leptomeningeal metastasis 4

CNS indicates central nervous system.

TABLE 2Characteristics of Assessable Patients With Brain Metastasis (N 5 52)


Men 31 (60)

Women 21 (40)


Site of metastasis

Brain metastasis 52 (100)

With other visceral sites 22 (42)

With nonvisceral sites only 30 (58)

Single lesion 23 (44)

Multiple lesions 29 (56)

Symptomatic 15 (29)

Asymptomatic 37 (71)

TABLE 3Results of Treatment in Assessable Patients With Systemic Metastasesand Brain Metastases (N 5 52)

Response No. of patients (%)

Treatment

Temozolomide 29

Temozolomide and immunotherapy 23

Response/SD, systemic metastases 13 (25)*

CR 1

PR 5

SD 7

Response/SD, brain metastasis at systemic response 11 (21)y

CR 3

PR 2

SD 6

Median duration of cerebral response [range], mo 7 [2–15þ]

CR indicates complete response; PR, partial response; SD, stable disease.

* Seven of 13 patients received temozolomide, and 6 of 13 patients received temozolomide and

immunotherapy.y Five of 11 patients received temozolomide, and 6 of 11 patients received temozolomide and immu-

notherapy.

TABLE 4Characteristics of Patients With Systemic andNeurologic Response (N 5 11)


Men 5 (45)

Women 6 (55)


Site of metastasis

Brain metastasis 11 (100)

With other visceral sites 4 (36)

With nonvisceral sites only 7 (64)

Single lesion 6 (55)

Multiple lesions 5 (45)

Symptomatic 3 (27)

Asymptomatic 8 (73)

308 CANCER January 15, 2007 / Volume 109 / Number 2

no neurologic symptoms. Six patients had a single

brain metastasis, and 5 patients had multiple brain

metastases. The median time to neurologic progres-

sion in these 11 patients was 7 months (range, from 2

months to �15 months). Two patients received cranial

RT for cerebral PD after a time to neurologic progres-

sion of 3 months and 5 months. One patient who pre-

viously had received WBRT for brain metastasis

received supportive care alone for a cerebral recur-

rence after a time to progression of 2 months. The

other 8 patients did not need specific treatment for

their brain metastases.

Among 40 patients with brain metastases and

extracranial PD, 29 patients had documented pro-

gression, and 2 patients had stabilization of brain

metastases; whereas, in 9 patients, follow-up MRI

brain scans were not obtained. Sixteen patients

received cranial RT, and 1 of those patients had a

documented response to RT.

SurvivalThe median overall survival for the entire group of

179 patients was 7.4 months (95% confidence inter-

val [95% CI], 6.4–8.4 months). The median survival

was 5.6 months (95% CI, 4.4–6.8 months) for the 52

patients with brain metastases who were evaluable

and 8.4 months (95% CI, 5.9–10.9 months) for the

other 127patients (log-rank P < .001). Among the 122

patients without CNS metastasis, 58 patients had

only skin, lymph node, soft tissue (American Joint

Commission on Cancer stage M1a), and/or lung me-

tastasis (M1b) (median survival, 10.8 months; 95%

CI, 6.5–15 months), and 64 patients had visceral me-

tastasis (M1c) (median survival, 6.8 months; 95% CI,

4.7–9.0 months; log-rank P < .0001) (Table 5, Fig. 1).

The major cause of death in the 11 patients who

responded was neurologic PD in 3 patients and

extracranial PD in 6 patients. One patient remained

alive, and 1 patient was lost to follow-up because of

emigration with neurologic SD after 5 months from

start of treatment. The major cause of death in the

40 patients who had brain metastases with extra-

cranial PD was extracranial PD in 17 patients, neuro-

logic PD in 12 patients, both extracranial and

intracranial PD in 10 patients, and it was unknown

in 1 patient.

ToxicityThe toxicity of temozolomide in the 52 evaluable

patients with brain metastases included Common

Toxicity Criteria (CTC) grade 3 or 4 leukopenia in 3

patients (6%) and CTC grade 3 or 4 thrombopenia in

3 patients (6%). Intracranial hemorrhagic complica-

TABLE 5Overall Survival and Survival by Subgroup as Defined by theMost Important Site of Metastatic Disease

Subgroup Median survival, mo 95% CI

Overall survival (N ¼ 179) 7.4 6.4–8.4

Site of metastasis

Skin, soft tissue, lung (n ¼ 58) 10.8 6.5–15

Brain metastases (n ¼ 53) 5.6 4.4–6.8

Other visceral sites 6.8 4.7–9.0

95% CI indicates 95% confidence interval.

FIGURE 1. This graph illustrates survival according to the most important site of metastasis.


tions were not observed. Immunotherapy did not

cause signs or symptoms of brain edema.

DISCUSSIONPatients who have systemic metastatic disease and

brain metastases have a grave prognosis; and, among

them, patients who have melanoma fare worse. From

the Radiation Therapy Oncology Group studies on

brain metastases in solid tumors, it was calculated

that the median survival was 4.2 months for patients

who had extracranial metastatic disease and a high

pretreatment performance status (recursive partition-

ing analysis [RPA] class 2); and, for patients who had

a Karnofsky index <70, the median survival was 2.3

months (RPA class 3).15 Patients with brain metasta-

ses from melanoma who received WBRT had a me-

dian survival of 2.3 months for RPA class 2 and 0.7

months for RPA class 3.16

The reported objective response rates of sympto-

matic brain metastases from melanoma to WBRT

range from 11% to 14%.2,7–10,16 These data indicate

that WBRT is of little benefit in the majority of

patients who have symptomatic brain metastases

from melanoma. In addition, the duration of such

treatment will take a substantial part of the rest of

these patients lives, and its side effects, like fatigue,

nausea, and hair loss, signify an additional burden

for these patients.

A few small, Phase II studies have addressed the

efficacy of cranial RT in combination with chemo-

therapy. In patients who had mainly asymptomatic

brain metastases, the combination of RT with temo-

zolomide produced an objective response rate of

9.7% and a median progression-free survival of 2

months,17 which does not seem any better than the

results from treatment with RT alone. In combination

with fotemustine or dacarbazine, responses were

observed in individual patients, but considerable tox-

icity also was reported.18,19

In the current study, we observed that most of

the patients who responded with their systemic dis-

ease also showed a response of their brain metasta-

ses. Neurologic stabilization or responses appeared

to be meaningful, with a median time to progression

of 7 months. In only 2 of the 11 stabilized or

responding patients, cerebral recurrence required

cranial RT. The long median time to progression of 7

months was striking but may be explained by the

small size of brain metastases in the study popula-

tion, the favorable performance status, and the pau-

city of neurologic symptoms. However, a clear

relation between brain tumor size or neurologic

symptoms and the time to progression has never

been reported. Choi et al. reported that survival did

not differ between asymptomatic, insignificantly

symptomatic, or moderately symptomatic patients

with brain metastases from melanoma; however, sur-

vival was significantly shorter in patients who had

major symptoms.8 In the same study, no difference

in survival was observed between patients with single

or multiple brain metastases. An analysis of 355

patients with brain metastases from melanoma indi-

cated that age >65 years, extracranial metastases, the

presence of neurologic symptoms, and multiple

brain metastases were negative prognostic factors for

survival.20 Among the 11 neurologically stabilized or

responding patients in the current study, 1 patient

was aged >65 years, all patients had extracranial

metastatic disease, 8 patients had no neurologic

symptoms, and 6 patients had a single brain metas-

tasis. The observed response rate of 9% and the sta-

bilization of �11% of brain metastases in the current

study are in line with the treatment results from a

Phase II trial of temozolomide for brain metastases

from melanoma that, similar to the current study,

did not require immediate irradiation and showed a

response rate of 6% and a stabilization rate of 26%.13

Patient- or disease-related characteristics that

distinguished patients with control of neurologic dis-

ease from nonresponders could not be demonstrated

in the current study. Therefore, stabilization or response

of extracranial metastatic melanoma to temozolo-

mide was the only predictor of control of neurologic

disease.

Fotemustine also has demonstrated activity in

brain metastases from melanoma. The response rates

of brain metastases to fotemustine as single agent in

Phase II studies ranged between 8% and 28%.21–24

However, in a recent, large, Phase III study that com-

pared fotemustine with dacarbazine in patients with

metastatic melanoma, the response of brain metasta-

ses was 5.9% after treatment with fotemustine versus

0% after dacarbazine.21 Anecdotal responses also

were reported after other cytotoxic regimens, predo-

minantly in patients with favorable characteristics

like solitary, small, or asymptomatic brain metasta-

ses. A response to cisplatin and dacarbazine was

reported in 2 of 18 patients (11%) who had brain me-

tastases, whereas the response rate among patients

without brain metastases was 13%.25 A combination

of temozolomide and docetaxel induced a PR in 3 of

8 patients with brain metastases from melanoma.26

Temozolomide has also been combined with tha-

lidomide because of the possible immunomodulatory

and antiangiogenic activity of thalidomide. The rate

of response of brain metastases to this combination

regimen was 12%, and the rate of stabilization in the


brain was 27%, although there was a high rate of vas-

cular complications (42%).20 A randomized Phase II

trial did not show differences in the low response of

brain metastases (overall, 1 response in 21 patients)

between temozolomide alone, in combination with

IFNa, or in combination with thalidomide.27 In addi-

tion, in the current study, no difference in response

was observed between patients who received temo-

zolomide alone or in combination with IL-2 and

IFNa. The response of extracranial metastatic disease

in the current study is in agreement with the results

from a Phase III study of temozolomide versus

dacarbazine for metastatic melanoma.11

The high incidence of brain metastases in meta-

static melanoma and the minimally effective treatment

of large and symptomatic brain metastases suggest

that screening for brain metastases in patients with

metastatic melanoma may be relevant. Early treat-

ment of asymptomatic brain metastases with cranial

RT may prevent them from becoming symptomatic

and, thus, may improve clinical outcome. However, it

is unknown how effective RT may be in patients who

have asymptomatic brain metastases from mela-

noma, and cranial RT has side effects that affect

quality of life. Moreover, screening for brain metasta-

ses may yield false-positive results. and it is obvious

that the vast majority of patients with advanced mel-

anoma and asymptomatic brain metastases will die

of progressive extracranial disease. The discrepancy

between the incidence of brain metastases from mel-

anoma at autopsy and in clinical series indicates that

a substantial proportion of brain metastases has

been unrecognized clinically and, thus, is irrelevant.

Therefore, screening for brain metastases in patients

with metastatic melanoma probably is not useful. In

the current study, screening for brain metastases was

undertaken because of the risk of a pathologic in-

crease in brain edema caused by immunotherapy.

Neurologic complications of immunotherapy in our

patients with brain metastases were not encountered.

Management of treatment was not influenced by the

finding of brain metastases on screening MRI scans.

This suggests that screening for brain metastases is

not indicated in patients who will be treated with

temozolomide for metastatic melanoma. However,

we cannot exclude the possibility that outcomes may

have been different with use of other cytotoxic drugs.

In contrast to other drugs, temozolomide penetrates

the blood-brain barrier. Brain metastases usually de-

velop behind an intact blood-brain barrier, and tu-

mor angiogenesis probably begins when a tumor

exceeds 1 mm in size.28 Accordingly, patients with

metastatic melanoma who respond to temozolomide

develop less CNS metastases as the first site of recur-

rence compared with responders to dacarbazine.14,29

These results also suggest that small lesions probably

are treated more successfully with temozolomide. We

did not observe intracranial hemorrhagic complica-

tions in the 13 patients who responded. Brain metasta-

ses from melanoma are notorious for their bleeding

tendency. An incidence of hemorrhage �40% has been

reported, and the risk increases along with the in-

creased size of metastatic lesions.4,30 The incidence of

intracranial hemorrhage was 27% in a study with

temozolomide plus thalidomide for brain metastases

from melanoma.8 In conclusion, it is feasible and ethi-

cal to treat patients who have advanced metastatic

melanoma, including small and minor symptomatic

brain metastases, with temozolomide alone and to de-

fer cranial RT.

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