Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma




A single-institution Phase I clinical trial was conducted to determine the maximum tolerated dose (MTD) and define the safety profile of temozolomide and capecitabine when used in combination to treat brain metastases from breast cancer.


Patients were eligible if they had bidimensionally measurable supratentorial or infratentorial brain metastasis from histologically confirmed breast carcinoma. Patients could have received up to 3 prior chemotherapy regimens. Temozolomide and capecitabine were administered concomitantly to 4 sequential cohorts at different dosing levels on Days 1–5 and Days 8–12, with cycles repeated every 21 days until disease progression.


Twenty-four patients with multiple brain lesions were treated, including 14 patients with newly diagnosed brain metastases and 10 patients with recurrent brain metastases. Only 1 patient was chemotherapy-naive. Fatigue and nausea were the most commonly observed toxicities observed at any dose levels. Significant antitumor activity was observed, with a total of 1 complete and 3 partial responses (18% objective response rate) in the brain. The median response duration was 8 weeks (range, 6–64 weeks) and the median time to progression in the brain was 12 weeks (range, 3–70 weeks). Neurocognitive function improved or remained stable in patients with a response or stable disease.


The combination of temozolomide and capecitabine is an active, well-tolerated regimen. The observed antitumor activity warrants further evaluation of this combination as an alternative to or in combination with whole-brain radiation therapy for the treatment of multiple brain metastases. Cancer 2006. © 2006 American Cancer Society.

It has been reported that 15% to 30% of patients with advanced breast cancer will develop brain metastases.1–3 Patients with multiple brain metastases have a poor prognosis, with a median survival of <1 year. There is currently no approved chemotherapy regimen for brain metastases, and the current standard of care involves whole-brain radiation therapy (WBRT) and control of symptoms with steroids and anticonvulsants.4 However, WBRT is associated with a high risk of neurotoxicity,5, 6 and some patients refuse such treatment. Furthermore, patients with recurrent metastases who have been previously treated with WBRT cannot tolerate further irradiation because of cumulative neurotoxicity.

A variety of chemotherapy regimens have been investigated in breast cancer patients with brain metastases. However, standard agents used to treat breast cancer, such as taxanes and anthracyclines, have demonstrated limited efficacy in the treatment of brain metastases.7 Therefore, new active regimens are needed. Temozolomide (Temodar; Schering-Plough, Kenilworth, NJ) is an orally administered alkylating agent that penetrates the blood-brain barrier and has minimal toxicity. Temozolomide in conjunction with radiation therapy is the current standard of care for primary glioblastoma.8 In addition, temozolomide has demonstrated activity in the treatment of brain metastases from a variety of primary tumors, including breast cancer.9–12 Capecitabine (Xeloda; Hoffmann-La Roche, Nutley, NJ) is an orally administered precursor of 5-fluorouracil (5-FU) and is currently used in treating metastatic breast and colorectal cancer. Although it has not been confirmed whether capecitabine crosses the blood-brain barrier, it has shown some activity in the treatment of brain metastases from breast cancer.13, 14

Because options are limited for patients with multiple brain metastases, especially those with recurrent metastases who have already received WBRT, this Phase I study was conducted to evaluate the safety and activity of temozolomide in combination with capecitabine. The primary objective of this study was to determine the maximum tolerated dose (MTD) of temozolomide and capecitabine when used in combination to treat patients with newly diagnosed or recurrent brain metastases from breast carcinoma.


Patient Selection Criteria

Patients were eligible for this study if they had bidimensionally measurable supratentorial or infratentorial brain metastasis from histologically confirmed breast carcinoma. Patients with newly diagnosed brain metastases who had declined radiation therapy and were neurologically stable or had tumor recurrence or progression after WBRT or stereotactic radiotherapy (SRT) were eligible. Patients could have received up to 3 prior chemotherapy regimens for systemic metastatic disease but prior treatment with temozolomide or capecitabine was not permitted unless there was no evidence of disease progression while using capecitabine. Patients were required to have a life expectancy of at least 8 weeks and to have a performance status ≤2 on the Zubrod scale.15 Other eligibility criteria included adequate renal function with a creatinine level <2.0 mg/dL, adequate liver function with an aspartate aminotransferase (AST) <1.5× upper limit of normal, bilirubin <1.2 mg/dL, adequate bone marrow function with platelets >100,000 mm3, hemoglobin >8 g/dL, and absolute neutrophil count >1,500 cells/mm3. Patients were not eligible if they had rapidly progressing visceral disease or other serious medical conditions.

Study Design

The primary endpoint of the study was to determine the MTD of the temozolomide and capecitabine combination, with secondary endpoints including response rate, duration of response, and neurocognitive function. Patients were removed from the study if they had a serious adverse event; the patient failed to comply with the dosing, evaluations, or other requirements of the study; the patient desired to withdraw from the study or became pregnant; or the investigator felt that it was in the best interest of the patient. Written informed consent was obtained from each patient before participation in the trial.


Patients received capecitabine orally starting at a dose of 1800 mg/m2/day in 2 divided doses, and temozolomide was given orally once daily at a starting dose of 75 mg/m2/day. Concomitant daily doses were given on Days 1–5 and Days 8–12, with cycles repeated every 21 days until disease progression. Sequential cohorts received capecitabine and temozolomide at escalated doses as shown in Table 1. Patients were treated until occurrence of unacceptable toxicity or evidence of progression of brain metastases. Dose-limiting toxicity (DLT) was defined as 1) any Grade ≥3 nonhematologic toxicity, including palmar-plantar erythrodysesthesia but excluding nausea and vomiting (unless Grade 4 vomiting occurred despite the use of antiemetics); 2) Grade 4 neutropenia lasting longer than 7 days, Grades 3 or 4 neutropenia at Day 21, or Grade 4 neutropenia accompanied by infection and/or fever requiring parenteral antibiotics; and 3) Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding. Once ≥Grade 2 toxicity was observed, treatment was halted until the toxicity resolved to Grade 0 to 1, at which time patients were allowed to resume at the same or at a lower dose level. Toxicities were graded using the National Cancer Institute Common Toxicity Criteria (version 2.0).

Table 1. Planned Dose Escalations for Phase I
Dose groupCapecitabine, mg/m2Temozolomide, mg/m2


Clinical evaluation

Before study entry, patients underwent a complete history and physical examination, including evaluation of performance status and weight. Baseline radiologic studies were performed to define the extent of cranial and extracranial disease. Laboratory studies included a complete blood cell count, urinalysis, blood chemistry levels, and a serum pregnancy test in patients of childbearing potential. Complete blood cell and differential counts were tested every week during the study. Toxicity was assessed on Day 1 and every 3 weeks.


Magnetic resonance images were obtained before and every 6 weeks during the study. The size of measurable lesions was reported as the sum of the products of perpendicular dimensions. A complete response was defined as complete disappearance of all clinically detectable lesions; a partial response was defined as a ≥50% decrease in tumor volume; a minor response was defined as a <50% decrease in tumor volume; and progressive disease was defined as a ≥25% increase in tumor volume or the appearance of new lesions, provided that steroid dose had not increased since the last evaluation period and no clinical deterioration had occurred.

Neurocognitive function testing

Patients underwent a baseline evaluation of their cognitive function and symptoms (n = 24) and an on-treatment assessment after approximately 1 month (n = 17), and a subset of patients was evaluated at the end of the study (n = 7). Neurocognitive tests were administered by trained psychometricians under the supervision of neuropsychology faculty. The tests included the Hopkins Verbal Learning Test (HVLT) for total recall, delayed recall, and immediate recognition16; the Controlled-Oral Word Association (COWA) test for verbal fluency17; Digit Span and Digit Symbol for measuring attention span and graphomotor speed, respectively18; Trail Making Tests A and B for visual-motor scanning speed and executive function, respectively19; and the grooved pegboard for fine motor dexterity.19 Standard deviations from the normative mean were calculated for each test (mean = 0; standard deviation = 1). Impairment on a test was defined as ≤1.5 standard deviations from the normative mean; only 7% of the general population would be expected to score in this range.

Quality-of-life assessment

Symptoms and quality of life were assessed by the M. D. Anderson Symptom Inventory (MDASI)20 and the Functional Assessment of Cancer Therapy-Brain (FACT-Br) scale.21 For this test and its subscales, z-scores were calculated based on normal values for the general cancer population reported by Cella and Nowinski20 Changes in test performance in the subset of patients seen at follow-up were analyzed by Student t-tests for paired samples with 2-tailed tests of significance.

Determination of the MTD

The MTD was defined as the dose that is most closely associated with a 25% rate of DLT in Cycle 1. Five dose levels, with the corresponding assumed toxicity levels, were ordered. Patients were entered in cohorts of 2, starting with dose level 0, and observed for DLT. Doses were decided by a continual reassessment method with an exponential dose-toxicity model.22 This approach modeled the dose-toxicity relation using a 1-parameter curve. A prior distribution was placed on the parameter before the trial. After each set of patients was treated and toxicity was observed, the distribution of the parameter was updated and the next dose level was selected based on the predicted toxicity. If dose level 0 resulted in 25% DLT, patients were reduced to dose level −1. No dose levels other than level −1 were skipped. A total of 24 patients (approximately 2 per month) were entered into the trial. The dose recommended by the program following the last patient was declared the MTD.



Twenty-four eligible patients were enrolled and the demographic and clinical characteristics of all patients are listed in Table 2. The median age was 50 years (range, 32–77 years), and >80% of patients had a Zubrod performance status of 0 or 1. Seven patients had received 1 prior chemotherapy regimen and 17 patients had received ≥2 prior regimens. A median of 4 cycles of therapy was completed (range, 1–16 cycles). Fourteen patients were treated for the first time for brain metastases and 10 patients were treated for recurrent brain metastases. Among the 10 patients with recurrent brain metastases, 8 had received prior WBRT, and the 14 patients with newly diagnosed brain metastases all declined WBRT. All patients had multiple metastases that were not amenable to surgical resection or stereotactic radiosurgery. Seventeen patients were taken off study because of disease progression in the brain, and 5 patients were taken off study because of disease progression in other organs. No patients were taken off study because of toxicity.

Table 2. Patient Characteristics
  1. ER indicates estrogen receptor; +, positive; PR, progesterone receptor; −, negative; WBRT, whole-brain radiation therapy.

Enrolled, no.24
Median age, y (range)50 (32–77)
Performance status, n (%)
 02 (8)
 118 (75)
 24 (17)
Hormone receptor status
HER-2 status
Prior chemotherapy regimens
New onset brain metastases14
Recurrent brain metastases10
Prior WBRT8


Nonhematologic toxicity was mainly ≤Grade 2. The most commonly reported adverse events were fatigue, nausea, vomiting, headache, and constipation (Table 3). Grade 3 fatigue occurred in 1 patient treated at dose level 1 and 2 patients at dose level 2. Only 2 of the events occurred in cycle 1. One of the patients in dose level 1 experienced fatigue postcycle 1 that was attributed to the patient's disease. The patient was rated with Grade 3 fatigue 7 days after study entry and entered the study with Grade 2 fatigue. A dose reduction was allowed for the Grade 3 fatigue and the drug was continued until confirmation of progressive disease (PD) at restaging. The other Grade 3 fatigue on cycle 1 was persistent until Day 1 of Cycle 2. Despite a 1-week waiting period before the initiation of Cycle 2, the fatigue level worsened and the patient was placed in a hospice with PD. The fatigue was not considered a toxicity of the drug, according to the subinvestigator, but evidence of PD.

Table 3. Most Common Adverse Events by Grade in Each Dose Group for All Cycles
EventNo. of patients
Dose level 0 (n = 6)Dose level 1 (n = 6)Dose level 2 (n = 8)Dose level 3 (n = 4)
Grade 2Grade 3Grade 4Grade 2Grade 3Grade 2Grade 3Grade 4Grade 2Grade 3
Fatigue50 5132 2 
Nausea30 2020 0 
Vomiting20 3130 2 
Headache11 0110 0 
Diarrhea20 0000 0 
Constipation11 0110 0 
Hand-foot syndrome20 0000 0 
Neutropenia 21   11 2
Thrombocytopenia00 0002 01

The most common hematologic adverse events were Grade 3/4 neutropenia (3 patients at dose level 0, 2 at dose level 2, 2 at dose level 3) and Grade 3 (2 patients at dose level 2, 1 at dose level 3); neither of these occurred in Cycle 1 and did not constitute a DLT by protocol definition. Although absolute neutrophil counts decreased to as low as 0.3 × 109/L at dose levels 0 and 2, which represents Grade 4 toxicity, the median neutrophil count was 1.6 × 109/L at dose level 3. There were no episodes of neutropenic fever or sepsis. There were 2 dose reductions. One patient in dose level 1 required a dose reduction because of Grade 3 fatigue. Her fatigue was felt to be related to progression of her disease and not related to the drug combination. Another patient at dose level 3 was reduced because of Grade 2 nausea. This patient's dose was reduced at her own request.


Evaluation of response was not the primary endpoint of this study. However, significant antitumor activity was observed in patients with either recurrent or newly diagnosed brain metastases. Twenty-two patients were evaluable for response. There were 1 complete and 3 partial responses, for an objective response rate of 18% (Table 4). Eleven (50%) patients had either a minor response or stable disease. The 1 patient who had a complete response and 1 of the patients who had a partial response had never received WBRT. The other 2 patients in whom a partial response had been documented had previously received WBRT. The remaining patients had evidence of disease progression or were not evaluable for response. Responses were observed at dose levels 0, 1, and 2, with the complete response observed at dose level 0 (1800 mg/m2 of capecitabine and 75 mg/m2 of temozolomide). The median response duration was 8 weeks (range, 6–64 weeks), and the median time to progression in the brain was 12 weeks (range, 3–70 weeks).

Table 4. Response by Dose Level
 Dose level 0 (n = 6)Dose level 1 (n = 6)Dose level 2 (n = 8)Dose level 3 (n = 4)Total (n = 24)
Complete response1   1
Partial response111 3
Minor response or stable disease235111
Progressive disease21137
Not evaluable 11 2

Neurocognitive Function

The percentage of patients who scored in the impaired range at baseline is presented in Table 5. Approximately half of the patients exhibited impairments in fine motor dexterity, 40% had impaired learning ability, and one-fourth had deficits in executive function and cognitive processing speed at baseline. However, none had deficits in excess of the general cancer population. After 1 month of treatment, significant improvements in attention span (P = .047) and emotional function (P = .016) were observed, suggesting that the treatment was not neurotoxic and may have had a beneficial effect due to improved tumor control. There was a trend for improved graphomotor speed (P = .09). In addition, there was a significant improvement in emotional function as measured by the FACT-Br (P = .016) and no increase in adverse symptoms in the MDASI. There were no significant differences between the baseline and end-of-study assessment on any measure, although the sample size (n = 7) may have been too small to detect a difference.

Table 5. Percent Impaired at Baseline (n = 24)
Cognitive domainPercent
Graphomotor speed17
Verbal fluency17
Visual motor speed25
Executive function23
Total recall42
Delayed recall29
Motor dexterity (dominant)50
Motor dexterity (nondominant)57
Physical symptoms0
Social support0
Emotional well-being0
Functional well-being0
Overall quality of life0


Patients with multiple brain metastases have limited treatment options, particularly those with recurrent brain metastases who have failed prior WBRT. The combination of oral capecitabine and temozolomide at the doses investigated in this Phase I trial was well tolerated in patients with brain metastases from breast cancer and demonstrated antitumor activity. Furthermore, neurocognitive function and quality of life improved in those patients who either had a response or stable disease in the brain. This study, like many others looking at neurocognitive function in patients with brain metastases,21 found a high prevalence of cognitive dysfunction before treatment, particularly in the domains of memory, executive function, cognitive processing speed, and motor functions. However, it appears that the treatment had no negative impact on cognitive function or quality of life and may even have had a beneficial effect in those patients who had not progressed at the time of the neurocognitive assessment. Therefore, this regimen appears promising and warrants further investigation.

Hematologic toxicity was manageable and consisted mainly of thrombocytopenia and neutropenia. The most commonly reported adverse events were nonhematologic and generally mild to moderate in severity; fatigue was the most common adverse event, which in some of these patients was considered to be related to progression of the disease. Notably, hematologic toxicity was not a major DLT with this regimen. Despite the occurrence of Grade 3 fatigue in 2 of 8 (25%) patients at dose level 2, the decision was made to enroll patients at dose level 3 to further evaluate the safety profile of this combination and to assess whether dose level 2 should be considered the MTD. Given that dose level 3 did not result in any DLTs (Table 3), we concluded that the MTD was not reached. Therefore, all dose levels tested appear safe.

Relatively few prospective studies have examined the activity of chemotherapy in patients with multiple brain metastases from breast cancer, and those studies that have been reported are small, uncontrolled Phase II studies or retrospective case series.3, 7 Controlled trials comparing chemotherapy with either supportive care or WBRT have not been performed. The bulk of the clinical experience is with cyclophosphamide and 5-FU-based regimens (e.g., cyclophosphamide, methotrexate, 5-fluorouracil [CMF] or cisplatin and etoposide [PE]), which have been shown to produce response rates ranging from 20% to 60%, including some durable complete responses.7 For example, 1 prospective study of CMF demonstrated a 54% response rate, including 1 complete response, and a median survival of 25 weeks.22 These studies suggest that brain metastases from breast cancer are responsive to chemotherapy. However, the activity of these standard chemotherapy regimens may be limited in the current era because many patients presenting with brain metastases have already been exposed to these agents either as adjuvant therapy or for the treatment of metastatic disease, and they may have developed resistance.23 Most studies of novel agents with activity in breast cancer have excluded patients with brain metastases. Therefore, there is a need to explore agents with good central nervous system (CNS) penetration and activity against breast cancer that may be effective in this setting.

Temozolomide has excellent CNS penetration and has demonstrated single-agent activity against brain metastases from a variety of solid tumors, including breast cancer.10–12, 24 In breast cancer patients who received single-agent temozolomide, objective response rates ranged from 0% to 44%.10, 11, 23 When stable disease was included, overall disease control rates (CR + PR + SD) ranged from 19% to 88%.10–12, 24 Oral capecitabine is also active against breast cancer and has demonstrated activity against brain metastases from breast cancer in patients who failed prior chemotherapy.13, 14 Given that these 2 agents each have single-agent activity in this setting and given that they have distinct mechanisms of action, they may have additive or synergistic activity when combined. Both the observed 18% response rate and the disease control rate of 68% in the present study compared favorably with historical data from studies with single-agent temozolomide.

Treatment with oral temozolomide and capecitabine offers several advantages over conventional therapies for multiple brain metastases and offers a viable alternative to WBRT in patients who have recurrent disease or refuse WBRT because of the known risks of neurocognitive deficits, brain atrophy, endocrine dysfunction, and dementia.5, 6 The convenience of oral therapy allows the patient to self-administer both drugs, thus providing some quality-of-life benefits, and the favorable safety profile of this regimen may provide advantages over other systemic chemotherapy regimens.

In summary, this study demonstrates that the combination of temozolomide and capecitabine is active and well tolerated and may provide an alternative to WBRT for patients with multiple brain metastases. The durable responses, favorable time to progression, and maintenance or improvement of neuropsychological function observed in this study suggest that this regimen has potential. Therefore, a study of this drug combination concomitantly with WBRT is warranted to further evaluate its efficacy and safety in patients with brain metastases.


We thank Ms. Janet Campbell for secretarial assistance and Mr. Thomas Estok for very helpful comments, suggestions, and feedback