CNS Metastases in Breast Cancer

Nancy U. Lin, Jennifer R. Bellon, Eric P. Winer

From the Departments of Medical Oncology and Radiation Oncology, Dana-Farber Cancer Institute; Brigham and Women's Hospital; and Harvard Medical School.  Journal of Clinical Oncology, Vol 22, No 17 (September 1), 2004: pp. 3608-3617


brain_chemo_lin1.gif (11278 bytes) brain_chemo_lin2.gif (10865 bytes)

Corticosteroids may offer symptomatic relief within hours by restoring arteriolar tone and reducing capillary permeability, thereby decreasing cerebral edema surrounding brain metastases. The usual starting dose is 4 mg every 6 hours, and may be preceded by a bolus, depending on clinical circumstances. The dose often can be tapered during definitive therapy.

Whole-Brain Radiotherapy
In patients with parenchymal brain metastases from breast cancer, whole-brain radiotherapy (WBRT) improves both survival and quality of life compared with corticosteroids alone, and produces a median survival of 4 to 5 months. The RTOG has examined several schedules of WBRT (ranging from 4,000 rad/4 weeks to 2,000 rad/1 week), and found no differences in overall survival. More dose-intensive regimens have generated disappointing results; thus the most common choice remains 30 Gy delivered in 10 fractions in the United States. Seventy-five percent to 85% of patients will experience improvement or stabilization of their symptoms after WBRT, with seizures and headache most effectively palliated. Motor loss is less effectively treated, and only 30% to 40% of patients achieve complete reversal of their presenting symptoms.

Numerous retrospective studies have found that surgical resection of intracerebral metastases is associated with improved outcomes relative to WBRT alone. However, patients treated with surgery tended to have single lesions, minimal extracranial disease, and better performance status than those who were treated with a nonsurgical approach. As described above, these factors have been associated independently with outcome in several multivariate models.

Three randomized trials have been performed to address the role of neurosurgery. Patchell   randomly assigned 48 patients with single brain metastases (10% with breast primaries) to surgery followed by WBRT versus WBRT alone. Patients in the combined arm experienced a longer duration of functional independence (38 v 8 weeks), and improved survival (40 v 15 weeks; P < .01). Noordijk  conducted a randomized trial of 63 patients (19% with breast primaries) that confirmed and extended these findings. Importantly, in this study, the benefit of combined-modality therapy was seen only in patients with stable or absent extracranial disease. Patients with progressive extracranial disease at study entry achieved a median survival of only 5 months, irrespective of the allocated treatment. One additional trial failed to demonstrate a survival or quality-of-life benefit.70 Nearly half of the patients in this trial had extracranial disease, and 10 of 43 patients randomly assigned to radiotherapy underwent surgical resection. Although the literature is limited and it is not entirely clear how the findings should be interpreted for women with advanced breast cancer, surgical resection should be considered seriously in patients with single metastases and stable or absent extracranial disease.

The role of surgery in the treatment of multiple lesions is far more controversial. Several groups have reported excellent single-institution results. In a retrospective study, Bindal  noted that patients who had all of their brain metastases resected did as well as those with solitary metastases, with a median survival of 14 months. Conversely, Hazuka et al73 found that patients with two or more brain metastases achieved a median survival of only 5 months. It should be noted that in the positive study by Bindal  nearly 20% of patients had a primary diagnosis of breast cancer, and 13% had a primary diagnosis of lung cancer. In the latter study, more than half of the patients had a primary diagnosis of lung cancer, and only one patient had a primary diagnosis of breast cancer. It is possible that differences in the behavior of the primary tumor are the source of the conflicting results of these two studies. Nevertheless, at present, given the morbidity of multiple craniotomies, surgery has a limited role in patients with more than one brain metastasis, except in situations when a large, symptomatic lesion is present.

Stereotactic Radiosurgery
During the last decade, stereotactic radiosurgery (SRS) has emerged as an appealing alternative to neurosurgery. SRS can be used to treat single or multiple lesions, and also can be used as salvage therapy following neurosurgery and/or WBRT.In two case series, SRS produced excellent results in patients with breast cancer (50% to 70% of whom had multiple brain metastases), with a median survival after brain diagnosis of 15 to 18 months, and median survival after radiosurgery of 7 to 13 months.

No randomized trial has compared SRS to surgery for the treatment of single brain metastases. Retrospective analyses have yielded conflicting results, likely because of patient selection. Bindal  examined the outcomes of patients treated with SRS (n = 31) versus surgery (n = 62) who were matched for their primary tumor (16% with breast carcinoma), age, performance status, extent of systemic disease, and number of brain metastases. In this study, both overall survival and freedom from neurologic death were superior in the surgical group. Conversely, a similar study from the Mayo Clinic showed no survival difference between groups. Auchter et al80 reviewed the outcomes of 122 patients (11% with breast carcinoma) who underwent SRS for a single brain metastasis. Patients were eligible for inclusion in this retrospective study if they met the eligibility requirements of the randomized surgical trial of Patchell  The in-field control rate was 85% at 1 year and the median survival was 56 weeks (comparable to the results reported with neurosurgery), leading the authors to conclude that SRS is equivalent to surgery for single brain lesions. In the absence of data from randomized trials, the choice of SRS versus surgery usually is based on the size and accessibility of the lesion, symptoms, and functional status of the patient. The risk of neurotoxicity and local failure increases with size, thus SRS should be reserved for lesions with a diameter of 3 cm or less. Surgery offers immediate decompression of large, symptomatic lesions. For small, asymptomatic lesions, it is reasonable to consider either SRS or surgery.

For the treatment of multiple lesions, SRS may lead to improved outcomes in comparison with historical controls, who mostly received WBRT alone. Although randomized trials have not demonstrated a clear survival benefit, it is important to recognize that neurologic progression can be devastating, and therefore functional status is also a relevant end point. In RTOG 95-08, 333 patients with one to three brain metastases were assigned to receive WBRT plus SRS versus WBRT alone (the proportion of patients with breast carcinoma is not reported).85 SRS did not provide a survival advantage among the subgroup of patients with two to three brain metastases. However, patients in the SRS arm were more likely to experience a sustained stabilization or improvement in their performance status (43% v 27% at 6 months; P = .03), and were more likely to maintain local tumor control (82% v 71% at 1 year; P = .01). There has been one randomized trial comparing SRS plus WBRT with WBRT alone limited to patients with multiple brain metastases. This trial was stopped early after accruing only 27 patients, when the rate of local failure at 1 year was found to be 100% after WBRT alone, compared with 8% in the combined arm. More recently, a review of 183 patients with nonmelanoma brain metastases (percentage with breast carcinoma not specified) treated with SRS at the University of California (San Francisco, CA) reported no difference in median survival by number of metastases. Until these results are confirmed, it seems reasonable in most cases to limit SRS to patients with one to three brain metastases, and who have controlled extracranial disease and adequate performance status.

Radiotherapy After Localized Treatment
Because WBRT is associated with late toxicities such as memory disturbances, difficulty with complex problem solving, ataxia, and urinary incontinence, and does not appear to improve overall survival after surgery or SRS, its routine use is highly controversial. However, the risk of late toxicity must be weighed against the risk of CNS relapse. In a randomized trial of 95 patients with single brain metastases (10% with breast carcinoma), postoperative WBRT did not extend survival, but did reduce brain recurrences (70% v 18%; P < .001) and deaths from neurologic causes. The results of numerous retrospective studies have been similar. Two studies looked specifically at the clinical consequences of intracranial relapse. Robinson   identified 119 consecutive patients (the percentage with breast cancer was not specified) treated with SRS, half of whom received postprocedure WBRT. Among the 22% of patients who experienced disease relapse after receiving SRS alone, more than half were symptomatic; the addition of WBRT did not appear to worsen the neurologic status of long-term survivors. Regine  observed the outcomes of 36 patients (six with breast cancer) treated with SRS alone. Intracranial relapse occurred in 47% of patients at a median of only 4 months after SRS; 71% of the patients were symptomatic at recurrence, and 59% presented with neurologic deficits. Of the patients that experienced disease relapse, 17% were unable to proceed to salvage radiotherapy (RT) because of their poor overall status.

Studies of breast cancer patients are needed because their extended survival relative to patients with other solid tumors increases both the risk of intracranial relapse and long-term therapy-related toxicities. On the basis of the available data, the decision to add WBRT after local therapy remains heavily debated, particularly for single brain lesions. As a result of this uncertainty, the American College of Surgeons Oncology Group has opened a randomized, phase III trial (Z0300) to examine the role of WBRT after SRS in patients with solid tumors who have one to three brain metastases.

The intact blood-brain barrier precludes the entry of most chemotherapeutic agents into the CNS, with the exception of small, lipid-soluble molecules. In addition, P-glycoprotein is highly expressed by the brain capillary endothelium and actively mediates the efflux of anthracyclines, taxanes, and vinca alkaloids. As a result, agents such as doxorubicin, cyclophosphamide, fluorouracil, paclitaxel, docetaxel, and vinorelbine, which are active against breast cancer, penetrate poorly into the CNS under physiologic conditions (Table above).  For this reason, it is widely assumed that chemotherapy is of limited efficacy in the treatment of brain metastases. However, the blood-brain barrier is frequently dysfunctional within brain metastases. Tumor vasculature tends to be relatively permeable, as evidenced by enhancement of lesions with water-soluble contrast agents. Therefore, many chemotherapeutic agents, although they are unable to penetrate the intact blood-brain barrier, may still achieve therapeutic levels within brain metastases. Indeed, responses to a broad variety of agents, most of which are too large or hydrophilic to cross the intact blood-brain barrier, have been described (Table 2).Few trials have explored the use of chemotherapy in patients with brain metastases from breast cancer. Most clinical trials of novel agents for breast cancer have excluded patients with known CNS metastases. The largest series comes from Rosner  who treated 100 women with a variety of regimens, most commonly cyclophosphamide, fluorouracil, and prednisone, or cyclophosphamide, fluorouracil, and prednisone plus methotrexate and vincristine. Despite the fact that none of these agents crosses the normal blood-brain barrier to a significant degree, both regimens produced a 50% response rate in the CNS with a median duration of response of 7 months. Boogerd  treated 22 patients with cyclophosphamide, methotrexate, and fluorouracil, or cyclophosphamide, doxorubicin, and fluorouracil, and reported a 59% response rate. These results strongly support the contention that the chemosensitivity of the tumor may be as important as the ability of a drug to penetrate the normal blood-brain barrier in determining response to therapy. However, the utility of the above-described regimens in the current era is limited because many women will have already been treated with these agents in the adjuvant setting.

Among the anthracyclines, both liposomal doxorubicin and idarubicin have been demonstrated to cross the blood-brain barrier. Liposomal doxorubicin has been used in a phase II study of 15 patients with recurrent high-grade gliomas. Although there were no objective responses, more than 50% of patients achieved stable disease for 3 months or more. Idarubicin is an orally bioavailable anthracycline that achieves high levels in brain tumor tissue. Idarubicin has demonstrated activity against systemic disease in patients with breast cancer, but is associated with a risk of cardiac dysfunction. There are no reports of responses of brain metastases from breast cancer to either agent. Moreover, many patients presenting in the current era with brain metastases have already received anthracycline-based adjuvant chemotherapy, making these agents less attractive in the setting of recurrent disease.

Despite its limited CNS penetration across an intact blood-brain barrier, fluorouracil has been a component of several effective regimens for brain metastases. More recently, capecitabine, an oral fluoropyrimidine, was reported to induce the dramatic regression of multiple brain metastases in a woman who had experienced disease progression in her CNS despite treatment with paclitaxel, tamoxifen, procarbazine, lomustine, fluorouracil, and thalidomide.

There has been increasing interest in the role of the platinums in the treatment of breast cancer. Stewart measured cisplatin levels at autopsy in brain tissue. Clinically relevant drug levels were present in brain metastases, yet were undetectable in adjacent normal brain, supporting the hypothesis that the blood-brain barrier is dysfunctional in brain metastases. In two prospective studies of patients with breast cancer, the combination of cisplatin and etoposide produced CNS response rates of 38% to 55%.129,130 There are no reports of carboplatin's activity against brain metastases from breast cancer. However, carboplatin may achieve slightly higher CNS concentrations than cisplatin, and is an active agent in systemic breast cancer. Furthermore, carboplatin has produced CNS responses in ovarian and lung cancer, both as a single agent and in combination with etoposide or paclitaxel.

Bendamustine, an alkylating agent, is active against systemic sites of breast cancer, producing a 27% objective response rate among heavily pretreated patients. There has been one case report of activity against brain metastases when given at standard doses. Temozolomide is an oral alkylating agent that readily crosses the blood-brain barrier. Among 72 breast cancer patients treated with temozolomide for brain metastases, five responses have been reported. For patients who have not previously received cranial irradiation, a more promising option may be concurrent radiotherapy with temozolomide.126,127 In a randomized, phase II trial of 52 patients with brain metastases, five of whom had a primary diagnosis of breast cancer, the combination of temozolomide and WBRT resulted in a higher objective response rate (96% v 67%; P = .017), improved neurologic function, and a trend toward improved survival compared with RT alone. However, temozolomide has minimal activity against systemic breast cancer, which is a major disadvantage because the majority of patients with CNS involvement have coexisting systemic disease.

In most circumstances, chemotherapy is reserved for patients whose CNS disease has progressed despite WBRT and/or SRS. The ability of a drug to penetrate the intact blood-brain barrier does not necessarily correlate with its activity against brain metastases. Therefore, the choice of therapy is guided by an agent's activity against breast cancer in general, with preference given to drugs that have been reported to produce objective responses in the CNS.