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The Oncologist, Vol. 8, No. 1, 69–75, February 2003
© 2003 AlphaMed Press

ORIGINAL PAPER
LUNG CANCER

Use of Temozolomide with Other Cytotoxic Chemotherapy in the Treatment of Patients with Recurrent Brain Metastases from Lung Cancer

Benjamin L. Eberta, Ewa Niemierkob, Kitt Shaffera, Ravi Salgiaa

a Departments of Adult Oncology and Medicine, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, Massachusetts, USA; b Commonwealth Hematology-Oncology, Concord, Massachusetts, USA

Correspondence: Ravi Salgia, M.D., Ph.D., Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, D1234B, 44 Binney Street, Boston, Massachusetts 02115, USA. Telephone: 617-632-3468; Fax: 617-632-4379; e-mail: ravi_salgia{at}dfci.harvard.edu


   LEARNING OBJECTIVES
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 Learning Objectives
Abstract
 Introduction
 Case Reports
 Discussion
 References
 
After completing this course, the reader will be able to:

  1. Identify appropriate treatments for patients with brain metastases from lung cancer with a consideration of the response rates of chemotherapy in phase II clinical trials.
  2. Describe the mechanism of action and the current clinical applications of temozolomide.
  3. Explain why temozolomide may have utility in combination with other cytotoxic chemotherapeutic agents for treating brain metastases from lung cancer.

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
 Case Reports
 Discussion
 References
 
The use of chemotherapy for the treatment of brain metastases arising from lung cancer has been limited by poor efficacy and high toxicity. Temozolomide, an orally bioavailable alkylating agent that crosses the blood-brain barrier, has activity against brain metastases from both small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) when used as a single agent, but response rates are low. Preclinical experiments and early clinical studies in other malignancies indicate that temozolomide may have additive or synergistic effects when used with other chemotherapeutic agents. We report a case of a patient with SCLC with recurrent brain metastases after treatment with multiple chemotherapeutic regimens and whole-brain radiation therapy (WBRT) who was treated with temozolomide (150 mg/m2 for 5 days in a 28-day cycle) and oral etoposide (50 mg/m2 for 10 days in a 28-day cycle). A second patient with NSCLC and brain metastases who progressed after treatment with chemotherapy and WBRT was treated with temozolomide (150 mg/m2 for 5 days in a 28-day cycle) and gemcitabine (1,000 mg/m2 weekly for 2 weeks in a 3- week cycle). In both patients, the temozolomide regimens were extremely well tolerated and resulted in dramatic and durable responses. The combination of temozolomide with other chemotherapeutic agents represents a promising strategy for treating patients with lung cancer and recurrent brain metastases and merits further study.

Key Words. Temozolomide • Lung cancer • Brain metastases


   INTRODUCTION
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 Learning Objectives
 Abstract
 Introduction
Case Reports
 Discussion
 References
 
Brain metastases are a source of significant morbidity and mortality and herald a poor prognosis in patients with metastatic lung cancer. Patients with small cell lung cancer (SCLC) have an incidence of brain metastases of 10% at diagnosis and 80% at 2 years [1]. Patients with non-small cell lung cancer (NSCLC) have an incidence of brain metastases of 20% at diagnosis and 40% at autopsy [2].

With improvements in the treatment of systemic disease and prolonged survival, the incidence of brain metastases is increasing [3]. The use of chemotherapy appears to alter the natural history of NSCLC, increasing the relative incidence of brain metastases [4–7]. Treatment of locally advanced NSCLC with chemotherapy followed by radiation therapy and/or surgery decreases the risk of visceral metastases outside the central nervous system (CNS). The addition of chemotherapy to radiation and/or surgery increases the risk of developing brain metastases from 15%-18% to 27%-32% [4–7]. In some studies, the CNS is the most common site of recurrence after combined-modality treatment, occurring in up to 47% of patients with recurrent adenocarcinoma of the lung [6].

In both SCLC and NSCLC, over 50% of patients with brain metastases present with multiple lesions [8]. The principle therapeutic modalities in treating patients with disseminated brain metastases are steroids and whole-brain radiation therapy (WBRT). WBRT carries risks of long-term sequelae, including progressive dementia and neuroendocrine dysfunction [9]. In SCLC, the duration of response is about 5 months, and progression is most often seen first in the CNS [3, 10]. Options for treatment of recurrent brain metastases are more limited, as retreatment with WBRT is not recommended [9].

Pharmacological therapy for metastatic disease in the CNS is complicated by the blood-brain barrier. A number of phase II clinical trials have demonstrated efficacy of various chemotherapeutic regimens in treating clinically apparent brain metastases arising from SCLC and NSCLC. Nevertheless, median survival for patients in these trials remains approximately 6 months [3]. Patients with recurrent metastases have often received multiple chemotherapy regimens and tolerate further treatment poorly. Novel and new chemotherapeutic regimens that have good efficacy against brain metastases, are well tolerated by heavily pretreated patients, and might prevent further brain metastases by crossing the blood-brain barrier and treating microscopic disease are therefore needed.

Temozolomide (Schering Corporation; Kenilworth, NJ) is a second-generation alkylating agent. With nearly 100% bioavailability, temozolomide is administered orally, most commonly once a day for 5 days in a 28-day cycle. Both temozolomide and dacarbazine are converted to the same active metabolite, 5-(3-methyltriazen-1yl)imidazole-4-carboximide (MTIC). Temozolomide is converted to MTIC spontaneously at physiologic pH, while dacarbazine requires hepatic p450 enzymes for conversion to MTIC [11]. Temozolomide readily crosses the blood-brain barrier, achieving cerebrospinal fluid concentrations that are approximately 30% of plasma concentrations in both animal and human models [12].

Two phase II clinical trials have demonstrated efficacy of temozolomide in the treatment of patients with NSCLC with brain metastases, but the response rates were only 8%-9% [13]. Potential sensitivity to temozolomide was also shown for brain metastases arising from SCLC. Preclinical data indicate that combinations of temozolomide with other chemotherapeutic agents may produce additive or synergistic responses [14]. Toxicity to temozolomide is very limited, with less than 5% of patients experiencing myelosuppression [11]. Temozolomide is therefore an excellent candidate for use in combination chemotherapy for the treatment of brain metastases arising from lung cancer.

We believe that the combination of temozolomide with other chemotherapeutic agents would have higher activity than either therapy alone against recurrent metastatic disease to the brain. We describe one case of a patient with SCLC and disseminated brain metastases treated with oral temozolomide and oral etoposide. A second case is presented of a patient with NSCLC and disseminated brain metastases treated with temozolomide and gemcitabine. In both cases, the patients responded to the temozolomide combinations.


   CASE REPORTS
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 Abstract
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 Case Reports
Discussion
 References
 
Patient 1
A 46-year-old female with a 50 pack-year history of smoking presented with a 1-cm mass in the right external auditory canal. A biopsy of the mass showed a poorly differentiated neuroendocrine tumor that, on immunohistochemistry, was positive for AE1/AE3, CAM 5.2, neuron-specific enolase, chromogranin, and cytokeratin (CK)7, and negative for CK20, keratin 903, leukocyte common antigen, L-26, CD3, BER-42, S-100, HMB45, MART-1, and CD99. Further staging revealed a 2.5-cm left upper lobe mass, bulky mediastinal and hilar lymphadenopathy, supraclavicular lymphadenopathy, and multiple ring enhancing lesions in the cerebellum and both cerebral hemispheres up to 2 cm in size. She was diagnosed with extensive-stage SCLC with metastases to the external auditory canal and CNS.

She was initially treated with eight cycles of carboplatin (area under the curve [AUC] 6 on day 1) and etoposide (100 mg/m2 on days 1-3) on an every-3-week cycle. In addition, she received WBRT (3,000 cGy in 15 fractions) in a German Helmet technique encompassing the brain and upper cervical cord to C2. Radiation was completed prior to cycle 3 of chemotherapy. She had a complete response to initial therapy.

Seven months after completing chemotherapy, she had a recurrence as evidenced by a new, left upper lobe lung nodule and a 1-cm adrenal nodule. She was treated with two cycles of irinotecan (60 mg/m2) and gemcitabine (1,000 mg/m2) on an every-3-week cycle, but restaging after two cycles showed progression of disease. Numerous brain metastases were observed by magnetic resonance imaging (MRI). She was subsequently treated with paclitaxel (175 mg/m2) every 3 weeks, but had progressive brain metastases after two cycles of therapy.

She was thereafter started on temozolomide (150 mg/m2 p.o. every day for 5 days) and etoposide (50 mg/m2 p.o. every day for 10 days, on a 28-day cycle). She did not receive any steroids during therapy. During treatment, she was able to work full time, including the days when she received chemotherapy. Her Eastern Cooperative Oncology Group (ECOG) performance status improved from 1 to 0 due to improved energy level and decreased shortness of breath. She was pretreated with ondansetron before each dose of chemotherapy and experienced no nausea, vomiting, or change in appetite. She had no significant myelosuppression or other treatment-related toxicity at these doses. After 2 months of therapy, a brain MRI showed a dramatic response with complete resolution of many lesions and only faint residual evidence of other lesions (Fig. 1Go). On a concurrent restaging computed tomography (CT) scan of the chest, her mediastinal adenopathy had decreased by approximately 50%.



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  		Figure 1. MRIs before and after treatment with temozolomide and etoposide for SCLC. Axial and coronal MRIs of the brain after administration of gadolinium compare the appearance of metastatic disease before and after treatment. A) Axial image just above the level of the orbits before treatment, showing three large lesions with abnormal enhancement, and low signal centrally suggesting necrosis within metastases. B) Axial image at a similar level after treatment showing only faint residual enhancement in the region of the largest of the lesions. C) Coronal image near the posterior horn of the lateral ventricles before treatment, showing two adjacent enhancing metastases in the cerebellum. D) Coronal image at the same level as in (C) after treatment showing complete resolution of the enhancing lesions.

 
With cycle 3, the dose of oral etoposide was increased from 50 mg/m2 to 75 mg/m2. The dose of temozolomide remained 150 mg/m2. Restaging after 4 and 6 months of treatment showed no significant growth of CNS lesions. Her thoracic disease also remained stable, but a chest CT scan after 6 months of therapy revealed partial collapse of the left upper lobe due to obstruction of the left mainstem bronchus and left upper lobe bronchus. This was treated with radiation therapy.

Patient 2
A 61-year-old female with a 5 pack-year history of smoking during high school presented with increasing shortness of breath. She complained of headaches, dizziness, blurring of her vision, and diplopia with left lateral gaze. A chest x-ray followed by a chest CT scan revealed a large left-sided pleural effusion, a left hilar mass, prevascular and aorticopulmonary window adenopathy, and numerous bilateral pulmonary nodules up to 5 mm. A head CT and subsequent brain MRI revealed diffuse metastases in both hemispheres, the brainstem, and cerebellum. She was admitted to the hospital with severe shortness of breath attributed to the large pleural effusion, and a thoracentesis was performed. Cytology from the pleural fluid was positive for adenocarcinoma. Immunostains of the cells were positive for keratin (AE/AK3), carcinoembryonic antigen, TTF-1, and CK7, and negative for CK20. She was diagnosed with stage IV NSCLC with disseminated, symptomatic brain metastases.

She was treated initially with WBRT (3,250 cGy total dose) followed immediately by carboplatin (AUC 6), and paclitaxel (175 mg/m2). During chemotherapy, she developed symptoms of clinical progression with worsening nausea and headaches. In addition, her shortness of breath increased, and she underwent a repeat thoracentesis and pleurodesis for an enlarging pleural effusion. A restaging MRI of the brain after four cycles of therapy (12 weeks later) showed an increase in the size and number of her brain metastases. A CT scan of the chest revealed a marginal improvement in her pulmonary lesions.

She was thereafter treated with temozolomide (150 mg/m2 orally on days 1-5, every 28 days) in combination with gemcitabine (1,000 mg/m2 weekly for 2 weeks in a 3-week cycle). This regimen was initiated 3 months after completing WBRT. Steroids were tapered after WBRT and were not given during treatment with temozolomide and gemcitabine. Her ECOG performance status was 2 before starting this regimen, 1 after the first cycle, and 0 after the second cycle. Nausea, headaches, and visual changes resolved entirely. She had required support with G-CSF, 300 µg for 7 days during treatment with carboplatin and paclitaxel, and G-CSF was continued with temozolomide and gemcitabine. After two cycles of treatment, a restaging brain MRI showed a dramatic resolution of brain metastases (Fig. 2Go). Brain MRI, chest CT scan, and performance status remained stable after four cycles of therapy.



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  		Figure 2. MRIs before and after treatment with temozolomide and gemcitabine for NSCLC. Coronal MRIs of the brain after administration of gadolinium compare the appearance of metastatic disease before and after treatment. A) Coronal image at the level of the brainstem before treatment showing at least four abnormal enhancing lesions consistent with metastases, located at the gray-white junction. B) Coronal image at the same level as A) after treatment. The lesions are much less evident, with only very faint residual enhancement. C) Coronal image at the level of the third ventricle before treatment showing several more enhancing lesions. D) Coronal image at the same level as in C) after treatment, showing resolution of most of the lesions and a decrease in size of the remaining lesion by at least 50% in diameter.

 

   DISCUSSION
Top
 Learning Objectives
 Abstract
 Introduction
 Case Reports
 Discussion
References
 
We report two cases of patients with lung cancer and recurrent brain metastases after treatment with chemotherapy and WBRT, each treated with temozolomide in combination with etoposide or gemcitabine. In both cases, the regimens were efficacious and well tolerated. One patient had SCLC and was treated with temozolomide and oral etoposide in a dosing schedule based on the results of a phase I study of patients with recurrent malignant gliomas [13]. A second patient was treated with temozolomide and gemcitabine. This is the first report for both regimens in the treatment of patients with brain metastases from lung cancer.

In both patients, the brain metastases responded more dramatically than the thoracic lesions. There are multiple possible explanations for this finding. It is possible that the brain metastases were more sensitive to chemotherapy than systemic lesions because the CNS tumors did not develop resistance to previous chemotherapy regimens due to the blood-brain barrier. Alternatively, the brain metastases in these patients may be inherently more sensitive to the temozolomide-containing regimens than the primary disease, or the systemic lesions could be inherently more resistant. Previous exposure to radiation may have sensitized the lesions to chemotherapy, although radiation was completed several months before starting chemotherapy.

Traditionally, treatment of recurrent brain metastases is very similar to the primary treatment of brain metastases [10]. Isolated brain metastases may be treated with surgery and stereotactic radiosurgery. The majority of patients, however, have multiple lesions. Once a patient has been treated with WBRT, retreatment is not recommended. Systemic chemotherapy can also be effective for the treatment of brain metastases, and is therefore an option for recurrent brain metastases [3, 15].

Many chemotherapeutic regimens have been used in phase II trials for the treatment of brain metastases arising from both SCLC (Table 1Go) and NSCLC (Table 2Go). Activity in the treatment of systemic disease correlates well with activity against brain metastases from lung cancer. Many of these regimens are toxic, with treatment-related mortality and dramatic effects on quality of life in these patients who have been heavily pretreated with chemotherapy and radiation. Among trials of patients treated for brain metastases from lung cancer, treatment-related mortality was observed in 7 of 13 patients treated with high-dose etoposide [16], in 8 of 80 patients treated with teniposide [17], and in 2 of 14 patients treated with cyclophosphamide, doxorubicin, vincristine, and etoposide [18].


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  		Table 1. Results of prospective trials for the treatment of SCLC
 

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  		Table 2. Results of prospective trials for the treatment of NSCLC
 
Temozolomide has several properties that make it an attractive candidate for incorporation into treatment regimens for brain metastases. It is orally bioavailable, facilitating administration; it is well tolerated, enabling it to be used in heavily pretreated patients and in combination with other agents; and it has excellent penetration of the CNS. Temozolomide reaches maximum concentrations in the plasma and CSF within 1-2 hours of oral administration. CSF concentrations are approximately 30% of plasma concentration [11, 12, 19].

Temozolomide has been approved by the Food and Drug Administration for the treatment of refractory anaplastic astrocytoma. Clinical efficacy of temozolomide has also been demonstrated in glioblastoma multiforme, melanoma, and a variety of other solid tumors [11]. Temozolomide, used as a single agent, has reported activity against brain metastases from melanoma [20]. Three phase II trials have been reported using temozolomide in patients with brain metastases from solid tumors [21–23].

A phase II trial was conducted at Memorial Sloan-Kettering Cancer Center in which 41 patients with recurrent brain metastases were treated with temozolomide 150 mg/m2 or 200 mg/m2 for 5 days in 28-day cycles, depending on whether they had been previously treated with chemotherapy [11]. Of the 22 patients with NSCLC, two had partial responses and eight had stable disease. In another trial, conducted by the Hellenic Cooperative Oncology Group, 24 heavily pretreated patients with brain metastases from solid tumors were treated with temozolomide 150 mg/m2 for 5 days in 28-day cycles [22]. One of 12 patients with NSCLC had a partial response, and two of five patients with SCLC had stable disease. In a randomized phase II trial performed by the Hellenic Radiation Oncology Group, patients with untreated brain metastases were randomized to receive WBRT alone or temozolomide 75 mg/m2 for 5 days in combination with radiation therapy [23]. Of the 48 patients in the study, 40 had lung cancer. The response rate was 67% for treatment with radiation alone and 96% for combined radiation and temozolomide.

Temozolomide might be useful in combination chemotherapy for several reasons. First, it is well tolerated with a low incidence of myelosuppresion, an important property for use in heavily pretreated patients. Second, temozolomide depletes O6-methylguanine-DNA methyltransferase, a DNA repair enzyme that is important for resistance to multiple chemotherapeutic agents. Third, temozolomide may recruit topoisomerase through methylation at the O6 position of guanine, theoretically potentiating the efficacy of topoisomerase inhibitors [14].

The use of temozolomide plus oral etoposide or gemcitabine in patients with brain metastases from lung cancer has not been reported. The combination of temozolomide and carmustine has additive or synergistic effects against malignant glioma in both preclinical and clinical studies [14]. Additive or synergistic effects have also been observed in patients with malignant glioma treated with temozolomide and irinotecan. Etoposide, cisplatin, paclitaxel, and topotecan have been tested in combination with temozolomide in phase I clinical studies of patients with malignant glioma or melanoma [14]. In a trial of temozolomide in combination with gemcitabine/cisplatin or gemcitabine/vinorelbine in patients with brain metastases from NSCLC, three of eight patients achieved a complete remission [24].

In summary, we report two cases of the combination of temozolomide with other cytotoxic chemotherapies (gemcitabine or etoposide) for treatment of recurrent brain metastases from lung cancer. It would be useful to determine the efficacy of these combinations in a larger clinical trial. Certainly, more therapies are needed for recurrent lung cancer in the brain. It would also be useful to determine if temozolomide could be combined with novel molecularly targeted therapies in lung cancer.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Case Reports
 Discussion
 References
 

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Received August 15, 2002; accepted for publication November 5, 2002.




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