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The Oncologist, Vol. 9, No. 1, 68–79, February 2004
© 2004 AlphaMed Press

ORIGINAL PAPER
Neuro-Oncology

The Role of Topotecan in the Treatment of Brain Metastases

Eric T. Wong, Anna Berkenblit

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

Correspondence: Eric T. Wong, M.D., Brain Tumor Center & Neuro-Oncology Unit, Department of Neurology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215, USA. Telephone: 617-667-1665; Fax: 617-667-1664; e-mail: ewong{at}bidmc.harvard.edu


   LEARNING OBJECTIVES
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Abstract
 Introduction
 Role of Topotecan in...
 References
 
After completing this course, the reader will be able to:

  1. Discuss the role of chemotherapy in the treatment of brain metastases.
  2. Identify the properties of topotecan that are conducive to treating patients with brain metastases.
  3. Discuss the investigation of single-agent topotecan and topotecan in combination with other chemotherapeutic agents or radiotherapy in the treatment of brain metastases.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
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 Learning Objectives
 Abstract
Introduction
 Role of Topotecan in...
 References
 
Despite advances in the treatment of systemic malignancies, the prognosis for patients with brain metastases continues to be dismal. Because the majority of cytotoxic agents seem to be unable to penetrate the blood-brain barrier, the role of chemotherapy in the treatment of brain metastases remains controversial. However, growing amounts of both laboratory and clinical data suggest that a few of the newly developed cytotoxic agents can cross the blood-brain barrier and may have a role in the treatment of patients with brain metastases. Topotecan, a novel topoisomerase I inhibitor, freely crosses the blood-brain barrier and may be clinically effective in both the therapeutic and prophylactic settings in patients with brain metastases. Recent studies have demonstrated the antitumor activity of topotecan against brain metastases, with objective response rates ranging from 33%-63% in patients with various solid tumors. The antitumor response in the central nervous system was often greater and occurred more quickly than the systemic antitumor response to topotecan treatment. This result may be explained by the lack of exposure of brain metastases to previous cytotoxic agents, suggesting a role for topotecan in patients with brain metastases. Early studies have also suggested that topotecan, an apparent radiosensitizer, may be particularly effective in combination with radiotherapy, the current standard of care for patients with brain metastases. In addition, preliminary data suggest that topotecan in combination with temozolomide (another cytotoxic agent that can cross the blood-brain barrier) may have synergistic antitumor activity against brain metastases. This review summarizes the available preclinical and clinical evidence for the role of topotecan in the treatment of brain metastases and concludes with three case studies.

Key Words. Brain metastases • Neoplasms • Drug therapy • Temozolomide • Topoisomerase I inhibitor • Topotecan


   INTRODUCTION
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 Learning Objectives
 Abstract
 Introduction
Role of Topotecan in...
 References
 
Approximately 10%-30% of adults with cancer develop brain metastases during the course of their disease [1–4]The incidence of brain metastasis is increasing, with an estimate of 97,800–170,000 new cases of brain metastases annually in the U.S. [1]. This increase has been attributed, in part, to superior neuroimaging techniques for early detection and to better treatments, resulting in longer survival times and, therefore, an increased likelihood of distant spread. The most common primary tumors responsible for brain metastases are illustrated in Figure 1Go [1]. Patients with lung cancer account for approximately 50% of brain metastasis cases. More specifically, up to 50% of patients with small cell lung cancer (SCLC) experience brain metastasis during the course of their disease [5]. Intracranial metastasis is present in an estimated 10%-20% of those patients at initial diagnosis and in 80% of patients at autopsy [6, 7]. Other primary malignancies, such as breast cancer, melanoma, and colon cancer, are also notable for their high propensity of metastasizing to the brain.



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  		Figure 1. Prevalence of brain metastases by primary tumor type. Data from Wen et al. [1].

 
Treatment strategies developed over the past several decades have slowly improved the outcomes of patients with brain metastases. Approximately one-third of these patients are alive 1 year after the initial diagnosis of brain metastasis. Favorable prognostic factors include the absence of systemic disease, age <60 years, good performance status, surgical resection, and fewer than three brain lesions [1, 8]. The natural history of untreated brain metastases is characterized by progressive neurologic deterioration and a median survival of 9.5 weeks, for patients with a solitary brain metastasis, or 5 weeks, for those with multiple brain metastases [9]. However, survival is primarily determined by the extent of systemic malignancy.

Role of Surgery and Radiation Therapy in the Treatment of Brain Metastases
A summary of the therapeutic options and expected outcomes for patients with brain metastases is provided in Table 1Go [1]. Important advances have been made in the past 2 decades in the management of patients with brain metastases using surgery, radiation therapy, and both surgery and radiotherapy. The most notable advance was observed in patients with solitary brain metastases in whom surgical resection followed by whole-brain cranial irradiation resulted in a median survival of 40 weeks, compared with 15 weeks in those treated with radiation alone [10]. Interestingly, patients in another study who had oligometastases to the brain underwent resection of all brain metastases followed by whole-brain cranial irradiation and did just as well as those with resection of solitary brain metastases and radiation therapy [11]. Although these data are retrospective, the findings suggest that surgical cytoreduction of brain metastases may be an important prognostic factor.


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  		Table 1. Therapeutic options and expected outcomes for patients with brain metastases
 
Whole-brain cranial irradiation alone extends the median survival of patients with brain metastasis to 3–6 months [1]. However, this modality of radiation can result in delayed, irreversible encephalopathy, characterized by attention deficits, gait imbalance, and urinary incontinence in adults [12] and decline in intelligence in children [13]. Because the daily dose per fraction of radiation appears to be an important determinant of these side effects, a lower daily fraction of 200–250 cGy can minimize or delay radiation-induced encephalopathy in patients with good prognostic factors and expected prolonged survival, compared with the customary 300- to 600-cGy fractions. Another alternative to whole-brain cranial irradiation is stereotactic radiosurgery. Patients with solitary metastases or oligometastases to the brain could benefit from stereotactic radiosurgery treatments up front and delay whole-brain cranial irradiation. The local tumor control rate reported by Alexander et al. was high after stereotactic radiosurgery, with an 85% control rate at 1 year and a 65% control rate at 2 years, and the toxicities associated with this procedure were minimal [14]. Shaw et al. noted grade 3 or higher neurologic toxicities in only 3% of patients with metastases measuring <=20 mm, in 10% of patients with metastases measuring 21–30 mm, and in 14% of patients with metastases measuring 31–40 mm in diameter [15].

Role of Chemotherapy in the Treatment of Brain Metastases
The primary hurdle in developing chemotherapy regimens for patients with brain metastases is that the normal, or intact, blood-brain barrier is largely impermeable to most drugs. However, the microcirculation of cerebral metastases most likely differs substantially from that of the normal blood-brain barrier and, therefore, the blood-brain barrier may be protecting only the normal brain tissue from chemotherapy. This is inferred from the leakage of gadolinium or iodinated contrast into brain metastases observed in magnetic resonance imaging (MRI) or computerized tomography (CT) scans, respectively. Nevertheless, considerable concern exists regarding patient exposure to cytotoxic agents that are associated with significant toxicity and may have limited effectiveness, which would decrease quality of life and be counterproductive for the patient with brain metastases.

Chemotherapy currently has a limited but increasing role in the treatment of brain metastases, particularly in patients with no evidence of systemic disease or in those who have been treated with cranial irradiation. However, treatment efficacy is determined by the sensitivity of tumor cells to chemotherapy drugs and whether or not these drugs can cross the blood-brain barrier. An objective response (OR) rate of 82% and a median survival time of 34 weeks [16] have been reported in patients with chemosensitive brain metastases from SCLC who were treated initially with cyclophosphamide, doxorubicin, vincristine, and etoposide. In patients with brain metastases from breast cancer at initial diagnosis, cisplatin and etoposide yielded a high OR rate of 55% in the central nervous system (CNS), whereas response rates of 17%-59% were seen in those treated with combination chemotherapeutic regimens that included: cyclophosphamide, doxorubicin, and prednisone; cyclophosphamide, doxorubicin, prednisone, methotrexate, and vincristine; methotrexate, vincristine, and prednisone; cyclophosphamide and doxorubicin; cyclophosphamide, methotrexate, and 5-fluorouracil; and cyclophosphamide, doxorubicin, and 5-fluorouracil [17–19]. Interestingly, an anecdotal report of the brain response of metastatic breast cancer to tamoxifen hormonal therapy suggests that the sensitivity of the primary malignancy to a particular agent is important [20]. In patients with recurrent or progressive brain metastases, the OR to systemic chemotherapy may be lower because of chemoresistance, as only 5.9% of patients treated with temozolomide had partial responses (PRs) and none had a complete response (CR) in the CNS [21].

Although the role of chemotherapy for brain metastases remains controversial, a new generation of chemotherapeutic agents that have the ability to cross an intact or physiologically normal blood-brain barrier holds promise for patients with brain metastases. Preliminary results indicate that topotecan (Hycamtin®; GlaxoSmithKline; Philadelphia, PA) and temozolomide (Temodar®; Schering-Plough Corporation; Kenilworth, NJ) have antitumor activity against both brain metastases and systemic primary malignancies. Topotecan is best characterized for its activity in SCLC, and its role in treating brain metastases deserves consideration.

Topotecan
Topotecan is a semisynthetic camptothecin derivative that selectively inhibits topoisomerase I in the S phase of the cell cycle, interfering with the replication and transcription processes in the tumor cell, which eventually leads to cell death. Topotecan is an established treatment in patients with recurrent SCLC, with overall tumor response rates >20% reported for extensive systemic disease in patients with good performance statuses [22– 25]. Furthermore, compared with cyclophosphamide, doxorubicin, and vincristine in the second-line setting, topotecan demonstrated significant symptom palliation for dyspnea, fatigue, and hoarseness in patients with recurrent SCLC [23]. Topotecan is also approved in patients with recurrent ovarian cancer [26, 27]. The activity, tolerability, and symptom improvements associated with topotecan have established the clinical value of topotecan in second-line therapy in patients with SCLC and ovarian cancer.

In addition to its well-established activity against primary tumors, topotecan freely penetrates the blood-brain barrier, and measurable levels of topotecan and its metabolite can be detected in cerebrospinal fluid (CSF) [28–31]. The emerging data suggest that systemically administered topotecan has antitumor activity against brain metastases. This review summarizes the preclinical and clinical data of topotecan for the treatment of brain metastases, including results of monotherapy and combined-modality studies. In addition, three case studies of topotecan in the treatment of parenchymal and leptomeningeal metastases are presented.


   ROLE OF TOPOTECAN IN BRAIN METASTASES
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 Abstract
 Introduction
 Role of Topotecan in...
References
 
Penetration of Topotecan Into the CSF
In both preclinical and clinical pharmacokinetic studies, topotecan has been shown to cross the blood-brain barrier [28–31]. In nonhuman primates, the mean CSF-plasma ratio of the active lactone form of topotecan exceeded 30% after an i.v. bolus of topotecan at 10 mg/m2 administered over 10 minutes, which is significantly greater than the CSF penetration of structurally similar camptothecins [29]. Furthermore, after an intraventricular bolus of 0.1 mg of topotecan, 46% of the active lactone form is cleared from the CSF by bulk flow, 44% by the conversion to the inactive hydroxy acid metabolite, and the remaining 10% by microvascular exchange with the plasma [28]. The unique ability of topotecan to pass the blood-brain barrier was attributed to its low protein binding in the serum—20% or less—relative to other campothecins that may be >95% protein bound [29].

Further pharmacokinetic data confirmed that topotecan crosses the blood-brain barrier in humans. In a phase I study of 17 pediatric patients with recurrent malignant brain tumors, topotecan was administered either as a single continuous i.v. infusion over 24 hours at a concentration of 5.5 or 7.5 mg/m2 per day or as a 72-hour continuous i.v. infusion at a concentration of 0.5–1.25 mg/m2 per day [30]. The median CSF-plasma ratio of the active lactone form of topotecan was 29% after a 24-hour continuous i.v. infusion and 42% after 72-hour continuous i.v. infusion. The CSF half-life of topotecan lactone was measured at 4.8 hours, and the clearance was 26.2 ml/hour/m2, suggesting that the clearance was primarily from CSF bulk flow. These data suggest that the duration of topotecan lactone presence in the CSF may not significantly differ among i.v. infusion rates (daily for 5 days, continuous for 24 or 72 hours) because of the high CSF clearance by CSF bulk flow [30].

In a pharmacokinetic study of an adult patient with breast cancer metastatic to the brain, Zamboni et al. [31] administered topotecan via a 30-minute i.v. infusion at doses of 1.5 mg/m2/day in cycle 1 and 1.0 mg/m2/day from days 1–4 in cycle 2 followed by a 4-hour i.v. infusion on day 5, both in a 21-day cycle. The plasma and ventricular pharmacokinetic tracings after the 30-minute and 4-hour infusions of topotecan are illustrated in Figure 2Go [31]. The CSF clearance of topotecan lactone after a 4-hour infusion was 20 ml/hour/m2, indicating clearance by CSF bulk flow in adults as well. Interestingly, the duration of topotecan lactone in the CSF at a cytotoxic concentration >1 ng/ml was 4.5 hours after a 30-minute i.v. infusion and was 7.5 hours after a 4-hour i.v. infusion [31]. However, data on the areas under the curve of topotecan lactone in the CSF from these two infusion schedules did not differ significantly. The clinical significance of this prolonged cytotoxic concentration of topotecan lactone in the CSF remains unclear. Additional CSF pharmacokinetic data of topotecan need to be determined in adult patients receiving topotecan in the U.S. Food and Drug Administration-approved dosing regimen—1.5 mg/m2/day as a 30-minute i.v. infusion on days 1–5 of a 21-day cycle.



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  		Figure 2. Penetration of topotecan into the CSF. Topotecan total plasma (left) and lateral ventricular (right) concentration versus time profiles after 30-minute ( and —) and 4-hour ({blacksquare} and - -) infusions. The horizontal bottom line on the lateral ventricular CSF concentration represents a topotecan concentration of 1 ng/ml in the CSF. Abbreviation: TPT = topotecan. Adapted from Zamboni et al. [31] with permission.

 
Alterations of Topotecan Clearance
Although 60%-70% of topotecan is excreted by the kidney [32], the remaining topotecan is metabolized in the liver. The clearance of topotecan can be altered by other agents that have an effect on the hepatic cytochrome P450 isoenzymes. Patients with brain tumors are susceptible to decreases in chemotherapy drug efficacy because of enzyme-inducing anticonvulsants, including phenytoin, carbamazepine, and phenobarbital, and other agents, including dexamethasone. These agents, which control seizures and neurologic symptoms, can increase the clearance of chemotherapeutic agents by activating the hepatic enzymes, particularly the cytochrome P450 isoenzyme CYP3A [33, 34]. When phenytoin was coadministered with topotecan in one patient with medulloblastoma, the clearance of total topotecan increased by 47% and the clearance of the active lactone form of topotecan increased by 45% [32]. Although there are limited data on the interactions between topotecan and hepatic-enzyme-inducing anticonvulsants and dexamethasone, it would be a prudent practice to use nonhepatic-enzyme-inducing anticonvulsants, such as lamotrigine, levetiracetam, and gabapentin, to control seizures. Likewise, the use of dexamethasone, a hepatic P450 enzyme inducer, should be minimized or avoided.

The Role of Single-Agent Topotecan
The pharmacokinetic profile and activity of topotecan in the treatment of solid tumors suggest that it may be effective in the treatment of brain metastases. Indeed, the potential antitumor activity of topotecan against brain metastases has been investigated in several studies (Table 2Go) [24, 35–40]. In a small, pilot study for newly diagnosed brain metastases from breast cancer, standard-dose topotecan at 1.5 mg/m2/day on days 1–5 of a 21-day cycle was administered in lieu of radiation therapy [35]. Of the 16 evaluable patients, six (38%) achieved an OR in the CNS, including one CR and five PRs. An additional five (31%) patients achieved stable disease (SD). The median overall survival time for all patients was 6.3 months. Although hematologic toxicity was the major toxicity, dose reduction was limited to three courses. Nonhematologic toxicity was rare and generally mild. The results of that study suggest that topotecan can safely be administered to patients with breast cancer previously treated with systemic chemotherapy without significant toxicity and can induce a response in brain metastases from breast cancer. Because breast cancer is generally chemosensitive, treating brain metastases from breast cancer up front with systemic chemotherapy and delaying whole-brain cranial irradiation may potentially obviate delayed radiation encephalopathy. However, further investigations are needed before this approach can become standard practice.


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  		Table 2. Studies of single-agent topotecan in the treatment of brain metastases
 
The antitumor activity of topotecan against brain metastases has also been demonstrated in patients with lung cancer (Table 2Go) [24, 35–40]. Topotecan monotherapy was evaluated in 20 SCLC patients with asymptomatic brain metastases after failure of first-line chemotherapy but without radiation therapy [36]. Eighteen patients received topotecan at doses of 1.5 mg/m2/day on days 1–5 of a 21-day course, and two patients received topotecan at doses of 0.4 mg/m2/day via a continuous 21-day i.v. infusion every 28 days. Brain metastases were monitored by CT scans on a bimonthly basis. Of the 16 evaluable patients, four (25%) had CRs, six (38%) had PRs, five (31%) had SD, and one (6%) had progressive disease in the CNS. The results of that study suggest that topotecan can induce a high OR rate in SCLC brain metastases and delay whole-brain cranial irradiation. However, the duration of the OR in that trial was short, and it is possible that new micrometastases were missed by CT scan because it is not as sensitive as MRI.

The role of topotecan as first-line treatment for newly diagnosed SCLC brain metastases is further supported by anecdotal observations. In a phase II study of patients with chemorefractory and chemosensitive SCLC treated with topotecan at doses of 1.5 mg/m2/day on days 1–5 of a 21-day cycle, 7 of 92 evaluable patients had documented brain metastases [37]. Of those seven patients, three with chemosensitive disease achieved CRs and one patient with chemorefractory disease achieved a PR within the CNS. An additional patient had a mixed response, with a 42% reduction in the target lesion and the complete disappearance of another nonmeasurable lesion. The most common toxicities were grade 3 or 4 leukopenia and neutropenia. In a similarly modeled phase II study, nine patients with chemosensitive SCLC brain metastases were treated with topotecan at doses of 1.5 mg/m2/day on days 1–5 of a 21-day cycle [24]. Brain tumor responses to topotecan were observed in five of nine (56%) patients, including four PRs and one CR in a patient receiving concurrent radiotherapy. Three patients had SD. Hematologic toxicity included noncumulative neutropenia; nonhematologic toxicity was uncommon and generally mild. The results from these two studies support using topotecan as a first-line treatment for newly diagnosed brain metastases in SCLC, particularly in platinum-sensitive patients. For patients who achieved only PRs, consolidative radiation may be necessary.

To more closely evaluate the potential for topotecan in the treatment of brain metastases, Schütte et al. [39] conducted a comprehensive retrospective analysis of the antitumoral responses to topotecan from various studies that had enrolled mostly patients with SCLC brain metastases. A total of 255 patients had been enrolled in the studies, including 247 with SCLC and eight with non-small cell lung cancer (NSCLC). Of 42 patients with documented brain metastases, 24 (22 SCLC and two NSCLC) had follow-ups and were evaluable. Patients received topotecan at doses of either 1.3–1.5 mg/m2/day via 30-minute i.v. infusions on days 1–5 of a 21-day cycle or 0.4 mg/m2/day as a continuous i.v. infusion over 21 days every 4 weeks. All patients were followed up every 2 months with CT and MRI. Of the 24 patients, 12 (50%) experienced ORs in their brain metastases (four CRs and eight PRs) and an additional eight patients had SD in the brain. The median duration of survival of the 22 evaluable patients with SCLC was 6.1 months. A comparison of the responses of cerebral and extracerebral lesions to topotecan treatment is provided in Table 3Go [38]. Interestingly, responses in the brain occurred more rapidly than extracranial tumor responses. This result may be explained by the lack of exposure of brain metastases to prior cytotoxic agents. Response or disease stabilization in the brain often occurred in patients with progressive extracerebral lesions, suggesting that cranial and extracranial metastases may have heterogenous topotecan sensitivities.


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  		Table 3. A comparison between responses of cerebral and extracerebral metastases to topotecan treatment
 
In a more recent multicenter study, Korfel et al. [40] enrolled 30 heavily pretreated SCLC patients with symptomatic brain metastases to evaluate the activity of topotecan in the treatment of brain metastases. More than half the enrolled patients had received platinum-containing regimens, and eight patients were treated with prior whole-brain radiotherapy (eight in the prophylactic setting and one in the palliative setting). The first 22 patients were treated with topotecan at doses of 1.5 mg/m2/day on days 1–5 of a 21-day cycle, whereas the last eight patients were treated with topotecan at doses of 1.25 mg/m2/day because of dose-limiting thrombocytopenia. The results of that study are summarized in Table 4Go [40]. The OR rate in CNS lesions was 33%, including three CRs and seven PRs. An additional eight (27%) patients had SD. The OR rate in systemic lesions was 29%. These data further suggest that topotecan is effective in treating brain metastases, even in patients previously treated with platinum-containing regimens.


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  		Table 4. Antitumor activity of topotecan in SCLC patients with brain metastases
 
Topotecan-Based Combinations in the Treatment of Brain Metastases
Synergistic antitumor activity against brain metastasis may be achieved when topotecan is combined with other cytotoxic agents with different mechanisms of action. However, the number of cytotoxic agents that can cross an intact blood-brain barrier is limited. Alkylating agents, such as carmustine and lomustine, are used in the treatment of primary brain tumors. However, tumors often rapidly develop resistance to these alkylating agents. Temozolomide, a third-generation alkylating agent, has an approximately 100% oral bioavailability, and it readily crosses the blood-brain barrier, reaching a CSF concentration that is approximately 30%-40% of the plasma concentration [41, 42]. Although temozolomide is only approved for the treatment of refractory anaplastic astrocytoma [43], its favorable toxicity profile has led to its off-label use in other types of malignant gliomas, including glioblastoma multiforme [44–46].

Preclinical studies have demonstrated mechanisms for the synergy of topoisomerase I inhibitors and alkylating agents. The alkylating agent N-methyl-N'-nitro-N-nitrosoguanidine, known to cross-link the alkyl groups in the O6 position of guanine, can recruit the topoisomerase I enzyme for repair activity and inhibit the religation step of topoisomerase I activity in vitro [47]. When the topoisomerase I inhibitor irinotecan was added after carmustine administration in athymic nude mice with malignant glioma xenografts, synergistic antitumor activity was observed [48]. Similarly, temozolomide methylates the O6 position of guanine, which probably leads to recruitment of the topoisomerase I enzyme for DNA repair. Adding irinotecan after administering temozolomide has also shown synergistic antitumor activity in xenografts implanted in immune-deficient mice [49]. There may be other mechanisms behind this synergism because the combination of irinotecan and temozolomide also demonstrated synergy in O6-methylguanine-DNA-methyltransferase-proficient and mismatch-repair-deficient tumors.

Because the combination of a topoisomerase I inhibitor with an alkylating agent has demonstrated synergy in preclinical studies [50], it has been hypothesized that the combination of topotecan with temozolomide may enhance the cytotoxic activity of these two agents. Therefore, a phase I study was designed to investigate the safety profile of topotecan in combination with temozolomide and to recommend a dosing regimen for future studies [51]. Twenty-five patients with various solid tumors received a total of 87 courses of topotecan and temozolomide at six dose levels, which were each administered daily for 5 consecutive days. Neutropenia and thrombocytopenia nadirs occurred consistently on day 15, and platelet counts recovered by day 28, with no patients requiring treatment delays past day 28 of a cycle. Dose-limiting febrile neutropenia was reported in two of five patients treated with topotecan at a dose of 1.5 mg/m2/day and temozolomide at a dose of 200 mg/m2/ day. Therefore, the recommended dosing regimen for phase II studies was 1.5 mg/m2/day of topotecan and 150 mg/m2/ day of temozolomide for 5 consecutive days. PRs were observed in three pretreated patients (colorectal cancer, NSCLC, melanoma). In addition, seven patients who completed three to seven cycles of therapy had SD. Results of this phase I trial suggest that the combination of topotecan and temozolomide is feasible and should be further explored in the treatment of brain metastases.

Topotecan in Combination With Radiotherapy
Previous in vitro studies have suggested that topotecan may act as a radiosensitizer; consequently, the combination of topotecan with radiotherapy may result in synergistic antitumor activity. Topotecan in combination with {gamma}-irradiation resulted in an additive effect of {gamma}-irradiation-induced cell killing in vitro [52]. Mattern et al. [53] also reported that subtoxic concentrations of topotecan potentiated irradiation-induced killing and exponential growth of Chinese hamster ovary and P388 murine leukemia cell lines. In vitro studies using HeLa S3 cells and a murine fibrosarcoma cell line reported a dose-dependent reduction in survival with a 4-hour exposure to topotecan after irradiation [52]. These early preclinical studies suggest that topotecan in combination with radiotherapy should be further explored and also suggest that clinical investigations of topotecan combined with whole-brain radiotherapy in patients with brain metastases may be warranted.

Concurrent chemoradiotherapy in patients with brain metastases has not been extensively investigated. The use of cisplatin, carmustine, and etoposide with whole-brain radiotherapy in patients with brain metastases from NSCLC and SCLC was investigated in a phase II, single-center trial [54]. Of the 60 patients enrolled in that study, 35 (58%) had CNS responses to therapy, 25 (42%) of those patients had CRs. The median survival time was 7.4 months; at 18 months the survival rate was 19%. A more recent randomized, phase III study using a combination of cisplatin and vinorelbine with whole-brain irradiation was also conducted in NSCLC patients with brain metastases [55]. Patients were treated with cisplatin and vinorelbine and whole-brain cranial irradiation either sequentially or concurrently. There was no significant difference in the intracranial overall response rates (27% in both treatment arms), median survival times (20 weeks versus 15 weeks), or progression-free survival times (14 weeks versus 8 weeks). This lack of efficacy may have been the result of the large molecular weight of cisplatin and vinorelbine, resulting in poor penetration across the blood-brain barrier. In both of those studies, the combination of chemotherapy with radiation was generally well tolerated, with myelosuppression being the most common toxicity. Although long-term neurocognitive toxicity associated with chemoirradiation regimens is unavailable from these early studies, they suggest that a combined-modality regimen of chemotherapy and radiation in patients with brain metastases is feasible. However, chemoirradiation using a drug with greater CNS penetration may offer superior efficacy in controlling brain metastases but may also increase the risk for acute and delayed neurotoxicities.

Very few studies have explored the combination of topotecan with radiation therapy for the treatment of brain metastases. Initial single-patient observations came from topotecan trials in patients with relapsed lung cancer. Schütte et al. [39] reported that one patient with brain metastasis from SCLC had a CR in the CNS after concurrent topotecan and radiotherapy treatments. Likewise, Depierre et al. [24] reported that one patient who received concurrent radiotherapy and topotecan had a CR within the CNS. These anecdotal observations provided a basis for topotecan chemoirradiation investigations for the treatment of brain metastases.

The feasibility of topotecan in combination with cranial irradiation was rigorously investigated in one phase I and one phase II study of patients with glioblastoma multiforme [56, 57]. In the phase I study, systemic toxicities, primarily hematologic, were tolerable up to the standard topotecan dose of 1.5 mg/m2/day in combination with cranial irradiation [56]. In the phase II study, patients received topotecan at doses of 1.5 mg/m2/day on days 1–5 of a 21-day cycle and standard cranial radiation therapy (60 Gy in 30 fractions over 6 weeks) [57]. Although there was no statistically significant survival advantage of this therapy over other therapies, the combination of topotecan and radiotherapy was generally well tolerated. Only two (2%) patients experienced grade 4 CNS neurotoxicity (decreased responsiveness) and four (5%) patients had grade 3 CNS neurotoxicity (headache, decreased motor function, confusion, agitation, hallucination, and visual disturbance) within 90 days of radiation therapy. Only two (2%) patients experienced delayed (>90 days) grade 3 CNS neurotoxicity.

In another phase I/II study, Grüschow et al. [58] investigated the feasibility of topotecan in combination with radiotherapy in patients with brain metastases. Patients were treated with a continuous i.v. infusion of topotecan at a dose of 0.4–0.6 mg/m2/day for 21 days in combination with whole-brain cranial irradiation (in 2.0 Gy/fraction). Of 13 evaluable patients, four had CRs, two had PRs, and six had SD within the CNS. Intracerebral recurrence was reported in two patients, 4 months and 9 months after irradiation, and one patient had intraspinal recurrence after cranial irradiation. This outcome compares favorably with the two previously cited studies of concurrent chemoirradiation in patients with brain metastases [54, 55]. However, this was only a small phase II study in patients with brain metastases from heterogenous primary malignancies. Nevertheless, there may be a topotecan radiosensitizing effect, and the ORs seen in clinical reports suggest that further studies of topotecan in combination with whole-brain radiotherapy are warranted.

Topotecan in the Treatment of NSCLC Brain Metastases
Unlike patients with SCLC, patients with NSCLC at high risk for developing brain metastases do not benefit from prophylactic cranial irradiation [59, 60]. In addition, systemic chemotherapy has not been effective for parenchymal brain metastasis in patients with NSCLC, a more chemoresistant disease than SCLC [61] and breast cancer [19]. Therefore, the treatment options for patients with NSCLC brain metastases have been limited. However, the penetration of topotecan into the CSF provides a rationale for the evaluation of this novel agent in the treatment of brain metastases in patients with advanced NSCLC.

Three Case Studies
We have treated three patients with NSCLC parenchymal brain metastases (one with concurrent leptomeningeal metastasis) who have benefited from topotecan therapy. A summary of these cases is provided in Table 5Go. All three patients had been treated previously with whole-brain cranial radiation therapy, and two had received prior chemotherapy for their systemic disease. These three patients received topotecan at doses of 1.25–1.5 mg/m2/day for 4 or 5 days of a 28-day cycle. Two patients did not present with brain metastases at diagnosis; those patients benefited the most from topotecan therapy—they had stable CNS disease for 8 and 41 months, respectively. The third patient presented with parenchymal brain metastasis at diagnosis of NSCLC and had stable CNS disease for 5 months while experiencing bone metastases and disease progression of the primary tumor. The MRIs for the three case studies before and after topotecan are shown in Figure 3Go. These cases suggest that topotecan may have antitumor activity against brain metastases in patients with advanced NSCLC, and the systemic administration of topotecan may provide a longer survival time and a superior quality of life in these poor-prognosis patients. However, prospective trials are necessary to fully characterize the efficacy of topotecan in the treatment of brain metastases from NSCLC.


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  		Table 5. Topotecan case studies in NSCLC
 


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  		Figure 3. Topotecan provides treatment benefit for patients with NSCLC. Representative MRI from patients treated with topotecan therapy. A) Appearance of subependymal enhancement that remained stable for 8 months; B) presence of linear and nodular enhancement in the conus and cauda equina that remained stable for 8 months; C) recurrent NSCLC and radiation necrosis; D) after 12 months of topotecan chemotherapy; E) solitary brain metastasis after sterotactic radiosurgery; F) solitary brain metastasis after resection, and G) new tumors after five cycles of topotecan chemotherapy. The patients who did not have brain metastases at initial diagnosis (patients 1 and 2) achieved the most treatment benefit from topotecan therapy.

 
In conclusion, preliminary results indicate that topotecan provides treatment benefit to patients with brain metastases. Single-agent topotecan, especially in patients with SCLC or breast cancer, has demonstrated excellent response rates against brain metastases and may be safely and effectively combined with whole-brain radiotherapy and other chemotherapeutic drugs that have the ability to pass the intact blood-brain barrier. In addition, the ability of topotecan to cross the blood-brain barrier suggests that it may have a prophylactic role against brain metastases in both first-line therapy and on relapse of systemic disease. Although the data supporting the use of topotecan in the treatment of brain metastases come mostly from phase II studies and anecdotal reports, the compelling nature of the results warrants additional studies. In particular, phase III studies of topotecan with stereotactic radiosurgery or whole brain cranial irradiation versus stereotactic radiosurgery or whole brain radiation alone in patients with brain metastases would be a logical first step to define the effect of topotecan on progression-free survival and quality of life in patients with brain metastases.


   ACKNOWLEDGMENT
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Supported by GlaxoSmithKline, Philadelphia, PA.


   REFERENCES
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Received May 13, 2003; accepted for publication October 14, 2003.




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