Hematol Oncol Clin N Am 20 (2006) 1287–1295

HEMATOLOGY/ONCOLOGY CLINICSOF NORTH AMERICA

Chemotherapy and the Treatmentof Brain Metastases

Scott Peak, MD, Lauren E. Abrey, MD*Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue,New York, NY 10021, USA

Brain metastases have traditionally been treated with a surgical or radio-therapeutic approach. Chemotherapy has been used occasionally assalvage therapy. The blood-brain barrier (BBB) excludes most chemo-

therapeutic agents, rendering many systemic options ineffective within the cen-tral nervous system (CNS). Intrathecal (IT) chemotherapies do not penetrateinto brain tissue or bulky parenchymal tumors and, as a result, are ineffectivein the treatment of brain metastases. However, some patients with brain metas-tases benefit from chemotherapy, and agents such as temozolomide or targetedtherapies like gefitinib have demonstrated activity. A better understanding ofthe biological behavior of brain metastases may lead to the development of ef-fective treatments for this common complication of systemic cancer. The pur-pose of this review is to discuss the biology of brain metastases, and provide anupdate on current chemotherapeutic strategies in use for patients with brainmetastases.

THE BIOLOGY OF BRAIN METASTASESThe formation of metastases from a primary tumor is a complicated process.Important routes for dissemination include hematogenous, lymphatic, and di-rect extension. The metastatic process also involves sequential steps of tumorinvasion, angiogenesis, and, finally, growth of tumor cells [1]. Because the pro-cess requires the circulating tumor cells to overcome many barriers, distantgrowth of metastatic clones often fails [2].

In the case of CNS metastases, this process is limited further by the BBB,which is known to form more of a barrier to circulating cells than other organs.As the gateway to the CNS, the BBB must be breached in order for metastasesto enter successfully. Important elements of successful invasion are thought toinvolve E-cadherin-catenin complexes, neurotrophins, urokinase-type plasmin-ogen activators, and matrix metalloproteases [1]. Production of pro-angiogenicfactors such as vascular endothelial growth factor (VEGF) may also stimulate

*Corresponding author. E-mail address: abreyl@mskcc.org (L.E. Abrey).

0889-8588/06/$ – see front matter ª 2006 Elsevier Inc. All rights reserved.doi:10.1016/j.hoc.2006.09.007 hemonc.theclinics.com

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angiogenesis and, ultimately, growth of tumor [1]. As a result, developing tar-geted therapies to block each of these steps may represent important new waysof treating metastases.

The primary tumor may suppress metastases by releasing factors that inhibitgrowth of distant metastases [1]. This endogenous inhibition depends on metas-tasis suppressor genes (MSG), which produce factors that preclude growth ofdistant clones [1]. One such MSG is called nm23, and is thought to phos-phorylate a kinase suppressor of Ras, resulting in decreased signaling of theextracellular signal-regulated kinase (ERK)/mitogen-activated kinase (MAPK)pathway [3]. nm23 has been shown to be suppressive in some, but not all,cell types tested, suggesting other factors make an important contribution in-cluding the environment surrounding the metastases [3]. Transfecting a wild-type MSG into clones of tumor cells has the potential to reduce growth ofoccult micrometastases. This could be important in patients with locallycontrolled disease where MSG transfection could prevent growth of microme-tastases that may be disseminated but not yet detectable with our best studies.Other genes such as KAI1, KiSS1, MKK4, and BRMS1 act in a variety of waysto function as tumor suppressors [3].

Model systems using cell lines from lung and colon adenocarcinoma havenow been developed that reliably reproduce brain metastases in the lab; thesestudies are performed by direct injection of cell lines into the carotid arteries ofmice [4]. Cell lines such as MDA-MB-231BR have been shown to metastasizeto the brain in all cases, yet metastases are not found in other organs [4]. Thislevel of specificity may facilitate molecular analysis as well as have the potentialto study targeted therapies in brain metastases.

Fidler and colleagues [5] developed models to study the biological basis forbrain metastases from melanoma. Two melanoma cell lines were used: K-1735preferentially grew metastases within brain parenchyma, whereas B16 pro-duced lesions in meninges or ventricles. The ability of K-1735 to proliferatewithin brain parenchyma may be related to its production of gelatinase A,thereby enhancing invasiveness. B16 did not produce significant amounts of ge-latinase A, which may explain its inability to invade brain parenchyma effi-ciently. The brain microenvironment may also influence growth of cancercells. Fidler and colleagues [5] found TGF-b1 and TGF-b2 both stimulatedgrowth of K-1735 cell lines, but inhibited growth of B16 cell lines. Last, the met-astatic potential of brain metastases was compared with tumor cells present out-side the CNS. Interestingly, human melanomas from lymph nodes or lung hadgreater metastatic potential and malignant behavior compared with cells takenfrom brain metastases [5]. These models reveal differences in the metastatic po-tential and aggressiveness of melanoma tumor cells, which may prove advan-tageous in developing new treatments.

There are experiments that describe a ‘‘niche’’ hypothesis in the generationof distant metastases [6]. Kaplan and colleagues [7] irradiated mice to destroybone-marrow cells and injected radiolabeled purified cells into the bone mar-row; the mice were then injected with lung carcinoma and melanoma cells,

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each radiolabeled as well. On days 12 to 14, bone marrow–derived cells arrivedin the lungs, but radiolabeled tumor cells failed to appear until day 18. Thissuggested tumor cells secrete a factor that stimulates bone marrow–derived cells to travel to distant sites such as the lungs, which then created amicroenvironment favorable for growth of metastases [6]. At least one proteinexpressed by bone-marrow cells, VEGF receptor 1 (VEGFR1), seems to be in-volved in this process. Mice treated with antibodies to VEGFR1 failed to de-velop these ‘‘niche’’ environments and, as a result, had no detectable growthof metastases [6]. Yano and colleagues [8] determined that expression ofVEGF correlated with angiogenesis and growth of brain metastases. Further-more, anti-sense VEGF inhibited production of VEGF, and diminished the fre-quency of brain metastasis formation [8]. Targeted therapies directed at VEGFor its receptor may prove useful in the treatment of brain metastases.

CHEMOTHERAPYThe role of chemotherapy in the treatment of brain metastases depends in parton the underlying chemosensitivity of the primary tumor. While surgery andradiotherapy (RT) are the mainstays of treatment, there have been a few excit-ing developments to suggest chemotherapy is effective in certain types of brainmetastases or in particular clinical circumstances. Introducing chemotherapyearly in the disease process may be especially helpful as certain types of metas-tases, such as small-cell lung cancer (SCLC), are more likely to respond to up-front chemotherapy. Chemotherapy administered in conjunction with RT mayhave a synergistic impact resulting in improved radiographic response or over-all survival. In addition, chemotherapy can be helpful if there are no furthersurgical or RT options for a patient, or for patients with asymptomatic brainmetastases detected by routine surveillance scans.

Initial ChemotherapyAlthough chemotherapy is not usually chosen as the initial treatment modalityfor brain metastases, there are several situations where chemotherapy may beappropriate. Numerous studies of SCLC have shown that patients with syn-chronous presentation of systemic and CNS disease will have similar responserates in the brain and solid organs to initial chemotherapy regimens [9–11]. ForSCLC this is a particularly important consideration as patients often have sig-nificant systemic symptoms requiring prompt treatment; systemic chemother-apy may be used to address both sites of disease effectively. Similarly, it maybe appropriate to initiate the best systemic therapy in a patient with symptom-atic systemic disease and asymptomatic brain metastases.

Concurrent Chemoradiotherapy and RadiosensitizersRadiosensitizers are theorized to enhance effects of RT. Similarly, chemother-apy administered in conjunction with RT may have additive, synergistic or ra-diosensitizing effects. Most radiosensitizers have proved ineffective in clinicaltrials but recent studies with modexafin gadolinium (MGad), efaproxiral, and

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temozolomide show promise (see Table 1). MGad increases levels of free radicalsthat are potentially toxic to cells, and also appears to concentrate selectively incancer cells [12]. Efaproxiral works as a modifier of hemoglobin to reduce affinityof oxygen thereby increasing oxygenation of tumor tissue and resulting ingreater radiosensitivity [13]. Concurrent temozolomide and RT have shownbenefit for patients with brain metastases and glioblastoma [14–16].

Suh and colleagues [13] reported results of a phase III trial analyzing the ben-efit of combining efaproxiral with WBRT. The trial included 515 patients, mostof whom had either non-small cell lung cancer (NSCLC) or breast adenocarci-noma as primaries, who were randomized to WBRT and received supplementaloxygen, with or without efaproxiral. The primary objective was overall survival,with secondary objectives including response rate. The median overall survivalwas 5.4 months for all patients treated with efaproxiral, 6.0 months for NSCLC/breast cancer patients treated with efaproxiral, and 4.4 months for the controlgroup; however, none were statistically significant. NSCLC and breast cancerpatients experienced a statistically significant 13% improvement in responserate with the addition of efaproxiral. One of the most common grade 3 adverseevents was hypoxemia (11%), which was treatable with supplemental oxygen.These results suggest possible benefit of efaproxiral during WBRT in patientswith NSCLC and breast adenocarcinoma with brain metastases [13].

MGad was studied as a radiosensitizer in a phase 1b/II trial by Carde and col-leagues [17]. In the phase II trial, MGad was combined with WBRT (30 Gy,10 fractions) in 22 patients. The radiologic response rate was 72%, but mediansurvival was only 4.7 months [17]. Mehta and colleagues [18] published datausing MGad and WBRT (30 Gy in 10 fractions in 25 patients). Radiologic re-sponse was 68%, while median survival was 5 months. In addition, Mehta andcolleagues [19] evaluated MGad with WBRT for brain metastases in a phase

Table 1Motexafin gadolinium and efaproxiral as radiosensitizers in brain metastases

Trial Agent WBRT HistologyResponserates (%)

Mediansurvival (mo)

Suh et al[13]

Efaproxiral þoxygen(4 L/min, NC)

30 Gy,10 fractions

All 46 5.4 (P ¼ .16)

NSCLC/breastcontrol

54 6.0/4.4 (P ¼ .07)

38 4.4Carde et al

[17]MGad 30 Gy,

10 fractionsAll 72 4.7

Mehta et al[18]

MGad 30 Gy,10 fractions

All 68 5.0

Mehta et al[19]

MGad 30 Gy,10 fractions

All 5.2 (P ¼ .48)

Abbreviations: MGad, motexafin gadolinium; NSCLC, non-small cell lung cancer.

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III trial in 401 patients, most of whom had NSCLC (n¼ 251) or breast adenocar-cinoma (n ¼ 75). There was no statistically significant difference in survival inthose who received WBRT and MGad (5.2 months) versus WBRT only (4.9months) or time to neurologic progression (9.5 versus 8.3 months). However,time to neurologic progression may have improved in the subset of patientswith NSCLC brain metastases, and this is currently being evaluated in a phaseIII clinical trial with only NSCLC patients and brain metastases [20].

Antonadou and colleagues [14] published results of a randomized phase II trialof previously untreated patients with brain metastases, the majority from breastor lung cancer, using concurrent temozolomide and RT followed by adjuvant te-mozolomide compared with RT alone. A statistically significant, higher objectiveresponse (OR) rate (96% versus 67%) and complete response (CR) rate (38% ver-sus 33%) were noted with temozolomide combined with RT. This regimen waswell tolerated, with no grade 3 or 4 myelosuppression [14]. More recently,Verger and colleagues [15] reported results of a phase II randomized trial oftemozolomide given concurrently with WBRT (30 Gy in 10 fractions) in patientswith brain metastases (mostly lung and breast cancer); 82 patients were enrolled,and improvement in progression-free survival (PFS) at 90 days was noted in pa-tients who received WBRT and temozolomide (72%) compared with thosetreated with WBRT alone (54%; P ¼ .03). Death from brain metastases wasalso greater in patients who received WBRT alone (69% versus 41%); theseresults are consistent with improved local control of brain metastases [15].

Temozolomide with concurrent SRS or WBRT has been studied in brain me-tastases from melanoma. Hofmann and colleagues [21] evaluated temozolomidein 35 patients with unresectable CNS metastatic melanoma. Temozolomide wasgiven as 200 mg/m2 on days 1 to 5 for a total cycle length of 28 days. This wascombined with either stereotactic radiosurgery (SRS) or WBRT in 22 of 35 pa-tients. Responses were complete (CR) in 3%, partial (PR) in 6%, and stable in26% of patients. Median survival was 8 months, with the longest being28 months. Thirteen patients did not receive radiotherapy either because theyrefused it, had previously been treated with it, or were not deemed adequatecandidates for it. Those patients with only temozolomide had a median survivalof 5 months while temozolomide concurrent with RT was 9 months; however,there was no statistically significant difference in survival for SRS or WBRT [21].

Chemotherapy at RecurrenceMost patients treated for brain metastases will eventually relapse or progress inthe brain. At CNS progression, many patients will have multiple metastasesand focal treatment options such as surgery or radiosurgery are not appropri-ate. In this setting, the use of salvage chemotherapy is a reasonable strategy forpatients with an adequate performance status, and a wide range of chemother-apeutic agents have reported efficacy.

Abrey and colleagues [22] conducted a phase II trial of temozolomide in pa-tients with recurrent or refractory CNS metastases. Forty-one patients receivedeither 150 or 200 mg/m2/day for 5 days, in a 28-day cycle; a variety of primary

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cancers were involved, including NSCLC, breast carcinoma, melanoma, SCLC,rectal, and ovarian/endometrial carcinoma in descending order of frequency.Two partial responses were seen, both from NSCLC, and 15 patients achieveddisease stabilization. Median survival was 6.6 months, and median time to pro-gression was 2 months (3.1 months for NSCLC, 2.7 months for breast) [22].This trial demonstrated activity of temozolomide in patients with CNS metasta-ses not eligible for additional surgical or radiotherapeutic options.

Temozolomide has also been used with some success to treat brain metasta-ses from melanoma. Temozolomide given as monotherapy for metastatic mel-anoma to the brain resulted in an objective response rate of 7% and a mediansurvival of 3.5 months [23]. A phase II trial of temozolomide and thalidomidein 26 patients with brain metastases noted a median survival of 5 months, andmost grade 3 to 4 toxicities were disease related [24].

Lassman and colleagues [25] evaluated systemic high-dose methotrexate(HD-MTX) for recurrent CNS metastases, including parenchymal and lepto-meningeal disease. Thirty-two patients were treated with intravenous (IV)HD-MTX (3.5 g/m2) every other week until progression; most of the patientshad breast adenocarcinoma (n ¼ 29). Twenty-eight percent had a partial re-sponse and 28% had stable disease, for a disease control rate of 56%, while44% progressed. Median survival was 20 weeks (range 2.9 to 135 þ). No grade5 toxicities were reported, and the most common grade 3 and 4 toxicities weremyelosuppression (21%) and increase in serum hepatic transaminases (9%)[25]. Cytotoxic cerebrospinal fluid (CSF) levels of MTX can be achieved fol-lowing systemic infusion of 3.5 g/m2 for a sustained duration of time [26]. Sys-temic HD-MTX is an option for select patients with recurrent CNS metastases.

Capecitabine has been reported effective, but only in case reports and not inany prospective, randomized controlled trials (see Fig. 1). Siegelmann-Danieliand colleagues [27] report a patient with disseminated breast adenocarcinomaand metastatic brain lesions previously treated with systemic chemotherapy

Fig. 1. Patient with breast adenocarcinoma and brain metastases before and after treatmentwith capecitabine.

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and WBRT; she received capecitabine, 2000 mg/m2/day on days 1 to 14, withno treatment on days 15 to 21, for a total cycle length of 21 days. Her perfor-mance status improved from a World Health Organization (WHO) score of3 to 0, and she had a radiographic CR based on CT scans. The patient received30 cycles; the only toxicity reported was a grade 1 to 2 hand-foot syndromeand the patient remained symptom-free at the time of publication [27]. A fewadditional case reports note similar success [28,29].

Biologic AgentsTargeted biologic therapies, including small molecules and monoclonal anti-bodies, are being developed for many different types of solid tumors. Therole of these agents in treating CNS disease is unknown, but some preliminarydata suggest that at least some of these drugs may hold promise for CNSmetastases.

Gefitinib is a small molecule epidermal growth factor receptor (EGFR) antag-onist that has been approved for the treatment of NSCLC. The effectiveness ofgefitinib in patients with brain metastases from NSCLC has been recently de-scribed by Choong and colleagues [30] in a patient with NSCLC and brain andleptomeningeal metastases. The patient had been heavily pretreated. Gefitinib(250 mg) was given daily, and the patient clinically improved in 3 weeks. After6 weeks of treatment with gefitinib, she regained ambulatory capacity and con-trol of bladder function; MRI scan showed significant reduction in enhance-ment. The authors performed molecular analysis of this patient’s tumor, andfound two mutations of the EGFR tyrosine kinase (L858R and E884K) thatcorrelate with greater sensitivity to gefitinib compared with wild-type EGFR[30]. Namba and colleagues [31] reviewed 15 cases of recurrent NSCLC withbrain metastases treated with gefitinib, and found an objective response rateof 60% and median survival of 8.3 months (range 1.8 to 15.7 þ).

Ceresoli and colleagues [32] prospectively studied gefitinib (250 mg) givendaily in 41 NSCLC patients with brain metastases. Thirty-seven patientswere treated with prior chemotherapy, while 18 had received WBRT previ-ously. Ten percent of patients had a PR with a median duration of13.5 months. Seventeen percent had stable disease, with a median durationof 4 months. No grade 3 or 4 toxicity was reported [32].

Blood-Brain Barrier DisruptionDevising novel therapies to bypass the BBB may prove crucial in the treatmentof CNS metastases [33]. For example, multidrug-resistant transporters (MDRT)such as P-glycoprotein act to export chemotherapy that has successfully circum-navigated the BBB. Studies using combinations of chemotherapy and MDRTinhibitors (valspodar; PSC 833) have shown a 90% reduction in tumor volumeof nude mice injected with glioblastoma multiforme (GBM) cells [33]. However,a caveat involves the reduction in CSF clearance of chemotherapeutic agentsthat also occurs with inhibition of MDRT; this may result in significant neuro-toxicity from treatment, and requires further study [33]. Additional options in-clude convection-enhanced delivery (CED), which infuses therapeutic agents

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into the tumor and its surrounding tissue. However, given the frequent multi-plicity of brain metastases, the expected benefit for CED is limited.

SUMMARYChemotherapeutic options for patients with brain metastases are limited. Whilesurgery and RT are the most effective therapies for patients with brain metas-tases, there have been some encouraging developments with chemotherapy.Perhaps a better understanding of the molecular biology leading to brain me-tastases will yield more promising therapies. Identifying ways of bypassingthe BBB to deliver effective therapies, but avoiding clinically significant toxic-ities, is an important area for exploration.

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