Journal of Neuro-Oncology

, Volume 85, Issue 2, pp 223–227 | Cite as

Capecitabine Therapy of Central Nervous System Metastases from Breast Cancer

  • Meltem Ekenel
  • Adilia M. Hormigo
  • Scott Peak
  • Lisa M. DeAngelis
  • Lauren E. Abrey
Clinical-patient Studies

Abstract

Central nervous system (CNS) metastases from breast cancer carry a poor prognosis. Systemic chemotherapy is often ineffective due to the impermeability of the blood-brain barrier (BBB) and inherent chemoresistance of CNS metastases. There are limited data supporting the use of capecitabine in this setting. Medical records of seven patients with brain metastases from breast cancer who received capecitabine treatment at Memorial Sloan-Kettering Cancer Center from 1994–2006 were reviewed. Treatment outcomes were analyzed retrospectively in those patients. Median time from breast cancer diagnosis to the development of CNS metastasis was 48 (18–165) months. Four patients had brain metastases alone, two patients had both leptomeningeal and brain metastases and one patient had leptomeningeal metastasis alone. Five out of seven patients had failed other treatment modalities before capecitabine. Three patients showed complete response (CR) and three patients had stable disease (SD) after capecitabine. The patient with leptomeningeal disease improved clinically, but refused repeat cerebrospinal fluid (CSF) studies. Median overall and progression-free survival from initiation of capecitabine was 13 and 8 months, respectively, for all patients. Capecitabine may achieve a CR and provide long-term control in patients with both leptomeningeal and parenchymal CNS metastases from breast cancer.

Keywords

Breast cancer Capecitabine Central nervous system metastases 

Introduction

Central nervous system (CNS) metastases in breast cancer patients are generally seen as a late complication of advanced disease. The incidence of CNS metastases have been reported to be as high as 30% in large autopsy series, but symptomatic disease is found in only 10–16% of patients [1, 2].

Treatment of CNS metastases is often difficult and options are frequently limited. Selected patients can be managed with surgical resection or stereotactic radiosurgery (SRS). However, metastases are often multiple and whole brain radiation therapy (WBRT) is required which offers effective but short-term palliation. Additional radiotherapy is not feasible for most patients with recurrent disease due to the risk of neurotoxicity [3].

Chemotherapy for the treatment of CNS metastases is limited by intrinsic drug resistance of the metastases and by the additional obstacle of the blood-brain barrier (BBB), which precludes the entry of water soluble chemotherapeutic agents into the CNS. In addition, p-glycoprotein is highly expressed by the brain capillary endothelium and actively mediates the efflux of some chemotherapeutic agents such as doxorubicin, cyclophosphamide, 5-fluorouracil (5-FU), paclitaxel, docetaxel, and vinorelbine [4, 5]. However, the BBB is at least partially disrupted at the site of a metastasis and the responses to a variety of chemotherapies which are hydrophilic have been described [5]. These results suggest that chemotherapy may have a role as salvage therapy in patients with recurrent disease.

Despite the limited penetration of 5-FU into the CNS, responses to capecitabine, an oral analog of 5-FU, have been reported [6, 7, 8, 9, 10, 11, 12, 13, 14]. We describe seven patients with CNS metastases from breast cancer treated with capecitabine chemotherapy.

Materials and methods

We retrospectively reviewed the data of seven women who were treated at Memorial Sloan-Kettering Cancer Center from 1994 to 2006. All patients had a confirmed histologic diagnosis of breast cancer by excisional biopsy or surgery of their primary lesion. Brain or leptomeningeal metastases were documented on gadolinium-enhanced magnetic resonance imaging (MRI) or by lumbar puncture (LP). Patients received capecitabine 1,000 mg/m2 twice daily for 14 days. Treatment cycles were repeated every 21 days. Radiographic responses were assessed with gadolinium MRI according to World Health Organization (WHO) criteria. This study was approved by our Institutional Review Board.
Fig. 1

Axial T1-weighted MRI images after gadolinium. (A) Enhanced dorsal pontine lesion before capecitabine. (B) Complete resolution of enhancing metastasis after seven cycles of capecitabine

Results

Median age was 38 years (range 34–54). Six patients underwent surgery for localized breast cancer and one patient had metastatic disease at initial diagnosis. Infiltrative ductal carcinoma was the primary pathology in five patients, and two patients had mixed lobular and infiltrative ductal carcinoma. Estrogen receptor (ER) and progesterone receptor (PgR) were both negative in only one patient. Her-2 was assessed by immunohistology and was 3+ in three patients, 2+ in two, negative in one and unknown in another. Prior therapy included cyclophosphamide, methotrexate and 5-fluorouracil (CMF) (40%), both anthracycline and CMF (20%), and anthracycline-based chemotherapy (40%) as adjuvant treatment. Only one patient was treated with neoadjuvant anthracycline-based chemotherapy due to locally advanced disease. Radiation therapy was delivered to all patients, including the two who underwent lumpectomy for early stage disease. After adjuvant radiation therapy, patients whose tumor expressed ER and/or PgR were placed on Tamoxifen. Before the diagnosis of CNS metastasis, six patients had one or more extracranial organ metastasis; only one patient developed CNS involvement as the first site of metastasis. Median time to CNS metastasis development was 48 (18–165) months after diagnosis of breast cancer. Brain metastases alone were present in four patients, two patients had both brain and leptomeningeal metastases and one patient had leptomeningeal metastasis only at initiation of capecitabine (Table 1).
Table 1

Characteristics of breast cancer patients with central nervous system metastases

  

Breast cancer history

Sites of metastasis before CNS

TTP

Location

Patient number

Age

Stage

Histology

ER/PgR/Her-2

Adjuvant CT/RT/HT

1

38

IV

IDC

+/−/3+

None

Lung, liver

35

Brain

2

47

I

IDC

−/−/3+

CMF/RT/None

Local, liver

76

Brain

3

35

IIA

IDC

+/+/2+

CMF/RT/Tam

Liver, bone, lung, supraclavicular LAP

72

Brain

4

34

IIIB

IDC

NA

Neoadjuvant AC+T/RT/Tam then letrozole and goserelin

None

18

Brain and leptomeningeal disease

5

54

IIIA

L&IDC

+/+/2+

AC+T/RT/Tam

Lung and bone

48

Brain and leptomeningeal disease

6

46

IIIA

L&IDC

+/+/−

A+CMF/RT/Tam

Lung and bone

165

Leptomeningeal disease (Positive cytology only)

7

34

IIIA

DCIS with multifocal IDC

+/+/3+

AC+T/RT/Tam

Liver

41

Brain

L: Lobular, IDC: Infiltrative ductal carcinoma, DCIS: Ductal carcinoma in situ, CT: Chemotherapy, RT: Radiation therapy, HT: Hormonal therapy, TTP: Time from the initial diagnosis to CNS progression in months, CMF: Cyclophosphamide, methotrexate, fluorouracil, AC: Doxorubicin, cyclophosphamide, T: Paclitaxel, Tam: Tamoxifen, LAP: Lymphadenopathy, ER: Estrogen receptor, PgR: Progesterone receptor, NA: Not applicable, CNS: Central nervous system

Capecitabine was given to treat recurrent CNS metastases in five patients who had prior radiotherapy and chemotherapy, and was the initial CNS regimen in two other patients. Three patients achieved a CR (Fig. 1) and three patients had SD following treatment. One patient improved clinically with capecitabine, but refused repeat LP for response assessment. Two CR patients were re-treated with capecitabine for subsequent recurrence of their CNS metastases; one achieved a partial response (PR) lasting five months and the other had a SD for 11 months. Capecitabine was well tolerated in the majority of patients with only two requiring a dose reduction for hand and foot syndrome (Table 2).
Table 2

Capecitabine treatment

Patient number

Total daily dose

Best CNS response

Regimens used for CNS (in order)

TTP

OS

Comments

1

3,500 mg

CR

Capecitabine

8

27

Goserelin was used through out all treatments

SRS

   

Gemcitabine and trastuzumab

   

2

3,500 mga

CR

WBRT

1st 14

44

SD after 2nd capecitabine

Temozolomide

2nd 11

 

PD after 3rd capecitabine

Thalidomide

3rd 5

 

Trastuzumab was used through out all treatments

SRS

   

Capecitabine

   

Capecitabine

   

Capecitabine and docetaxel

   

Gemcitabine

   

3

3,500 mg

SD

SRS

7

13

 

WBRT

   

Capecitabine

   

Vinorelbine

   

Gemcitabine

   

4

3,000 mg

SD

WBRT

15

18

 

Capecitabine

   

IT MTX

   

5

3,000 mg

SD

IT MTX

12

12

 

WBRT

   

SRS

   

Capecitabine

   

6

3,500 mg

NA

Capecitabine

6

6

Clinically symptoms resolved

7

3,500 mga

CR

WBRT

1st 5

12

PR after 2nd capecitabine

Temozolomide

2nd 5

 

Letrozole and trastuzumab were used through out all treatments

Partial BRT

   

Craniotomy

   

High dose MTX and gemcitabine

   

Capecitabine

   

Capecitabine

   

IT: Intrathecal, WBRT: Whole brain radiation therapy, BRT: Brain radiation therapy, MTX: Methotrexate, SRS: Stereotactic radiosurgery, CR: Complete response, SD: Stable disease, PR: Partial response, CNS: Central nervous system, TTP: Time to progression in months, from capecitabine, OS: Overall survival in months, from capecitabine, NA: Not assessed

a Dose reduction

Two patients continued to receive trastuzumab throughout their chemotherapy regimens. One of those patients also received letrozole along with trastuzumab and one patient was on goserelin during her entire treatment without interruption. For all seven patients, median overall and progression-free survival from capecitabine chemotherapy was 13 months and eight months, respectively. Three patients expired during follow up due to their progressive systemic and CNS disease.

Discussion

The efficacy of capecitabine in brain metastases from breast cancer has been reported in isolated patients [6, 7, 8, 9, 10, 11, 12, 13] (Table 3); however, the larger phase II and III studies of capecitabine in metastatic breast cancer excluded patients with brain metastases. There is a single phase I study that combined temozolomide and capecitabine in breast cancer patients with metastases to the brain. In this study, Rivera et al. [14] suggested that this combination was active and well-tolerated and may provide an alternative to WBRT for patients with multiple brain metastases. However, the single agent activity of the two individual drugs, temozolomide and capecitabine, against CNS metastases from breast cancer is not known.
Table 3

Case reports of capecitabine in breast cancer patients with central nervous system metastases

Age

ER/PgR/Her-2

TTP

Location

Total daily dose and schedule of capecitabine

Best radiologic CNS response to capecitabine

Reference

54

−/−/+

17

Brain and leptomeningeal disease

2,400 mg/day 3 weeks on and 1 week off and WBRT

CR

6

42

+/NR/NR

132

Leptomeningeal disease

3,000 mg/day 2 weeks on and 1 week off

PR

7

41

−/−/NR

168

Brain and leptomeningeal disease

3,000 mg/day 2 weeks on and 1 week off

PR

8

38

−/−/NR

23

Leptomeningeal disease

2,500 mg/m2/day 2 weeks on and 1 week off

1st attempt CR 2nd attempt PD

9

53

+/+/−

42

Brain

2,000 mg/m2/day 2 weeks on and 1 week off

CR

10

37

−/−/+

36

Brain

2,000 mg/m2/day 2 weeks on and 1 week off

PR

11

51

−/−/−

30

Brain and leptomeningeal disease

1,000 mg/m2/day during WBRT then 2,500 mg/m2/day 2 weeks on and 1 week off

1st attempt and 2nd attempt CR

12

40

+/NR/+

76

Brain

2,500 mg/m2/day 2 weeks on and 1 week off

PR

13

ER: Estrogen receptor, PgR: Progesterone receptor, NR: Not reported, TTP: Time from the initial diagnosis to CNS progression in months, CNS: Central nervous system, CR: Complete response, PR: Partial response, PD: Progressive disease, WBRT: Whole brain radiation therapy

Our study combined with other reports in the literature suggests that capecitabine may have an effect as a single agent. Giglio et al. [9] and Tham et al. [12] reported that capecitabine in this patient population demonstrated clear radiographic response and survival ranging between nine months and 3.7 years. Among our patients, more than one-half had a radiographic or clinical response and the longest survival was 44 months. Furthermore, capecitabine may retain efficacy at subsequent recurrence of CNS metastases. Reintroduction of capecitabine to patients who had a prior response achieved a second remission in two of our patients. In the literature, one patient had a favorable response while a second failed to respond after reintroduction of capecitabine [9, 12].

One limitation of our series and others in the literature is the concomitant administration of other anti-cancer drugs. Two of our patients received trastuzumab during all their chemotherapy regimens including the capecitabine. It is difficult to assess whether continuing trastuzumab had any effect on CNS response in those patients; however, there are a number of reports in the literature suggesting that patients on trastuzumab may be at increased risk for the development of CNS metastases and it seems unlikely that trastuzumab improved CNS control in our patients. Church et al. [13] reported a patient in whom sequential addition of systemic chemotherapy, including capecitabine to continued trastuzumab, resulted in multiple tumor responses.

Current understanding of the pharmacokinetics of capecitabine and its metabolites in brain tumor tissue and CSF are limited. Penetration of this drug through the human BBB may occur via the human concentrative nucleoside transporter (hCNT). Thus far, two isotypes of hCNT have been identified at the cDNA level. hCTN1 is involved in transportation of pyrimidine nucleosides, whereas hCNT2 is a purine preferring transporter. hCNT1 is present in the rat BBB, but it has not been studied in human brain tissue. The metabolite of capecitabine, 5-deoxy-5-fluorouridine (5-DFUR), but not capecitabine itself or 5-FU, is an hCNT1 substrate. This transporter is responsible for the penetration of capecitabine through the BBB and confers its sensitivity to the drug [15]. In addition, the neurotoxicity of high dose 5-FU and capecitabine (reported as 0.1–0.5% in the package insert) is also indirect evidence that drug can penetrate the BBB in humans to a limited degree [16].

It is also possible that capecitabine transfer is enhanced if the BBB has been damaged secondary to WBRT. However, in our study, capecitabine resulted in a radiographic CR in one patient with brain metastasis and clinical improvement in another patient with leptomeningeal disease both of whom were radiotherapy naive. Rogers et al. [7] and Fabi et al. [11] have also demonstrated tumor regressions in brain and leptomeningeal metastases with capecitabine prior to WBRT.

In conclusion, this study demonstrates that both leptomeningeal and parenchymal disease from breast cancer can be successfully treated and controlled over a long period of time with systemic capecitabine therapy. In contrast to other treatment modalities, such as WBRT and intrathecal methotrexate, capecitabine is well tolerated and has no associated neurologic toxicity. Capecitabine may be an appropriate treatment alternative for patients with CNS metastases, particularly at time of tumor recurrence.

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Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Meltem Ekenel
    • 1
  • Adilia M. Hormigo
    • 1
  • Scott Peak
    • 1
  • Lisa M. DeAngelis
    • 1
  • Lauren E. Abrey
    • 1
  1. 1.Department of NeurologyMemorial Sloan-Kettering Cancer CenterNew YorkUSA

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