Resolution of extensive leptomeningeal metastasis and clinical spinal cord compression from breast cancer using weekly docetaxel chemotherapy
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- Wilson, B., Sapp, C., Abdeen, G. et al. Breast Cancer Res Treat (2012) 131: 343. doi:10.1007/s10549-011-1825-3
Metastatic breast cancer to the leptomeninges is a late event in the disease course and is associated with significant morbidity and a grave prognosis. Treatment typically involves direct intrathecal injection of chemotherapy into the cerebrospinal fluid compartment since systemic chemotherapy penetrates poorly to the central nervous system. Here we report an interesting clinical observation involving a patient presenting with leptomeningeal spread of breast cancer causing extensive spinal cord compression with obliteration of the subarachnoid space, thus precluding the use of direct intrathecal chemotherapy. We administered systemic chemotherapy using weekly docetaxel with complete radiographic resolution of her disease and recovery from clinical spinal cord compression. While this is a single clinical observation, weekly administration of docetaxel in this circumstance may have been associated with improved drug “escape” into the central nervous system and better antitumor effect. Because leptomeningeal disease is typically a late event in metastatic breast cancer, resistance to therapeutic intervention may reflect intrinsically resistant disease in the setting of extensive prior therapy rather than a routine problem with systemic drug delivery to the CNS. Studying patterns of disease relapse in patients who had received adjuvant weekly taxanes may provide insights into this hypothesis.
KeywordsBreast cancer Leptomeningeal carcinomatosis Chemotherapy Docetaxel
Leptomeningeal metastasis is a relatively late event in the course of breast cancer disease relapse and is typically associated with exceptional morbidity and a grave prognosis . Systemic therapy, in general, is known to have limited efficacy in the treatment of breast cancer metastatic to the central nervous system (CNS), presumably due to inadequate CSF penetration . Available data on the efficacy of anticancer drugs in CNS and leptomeningeal metastasis is largely anecdotal, and very limited data exist on potential effect of taxane therapy in this circumstance. Here we report an interesting observation of complete radiologic and clinical resolution of extensive leptomeningeal metastases from breast cancer using docetaxel administered on a weekly schedule and suggest an alternative explanation for the poor response to treatment typically seen in leptomeningeal disease.
A 55-year-old lady with a known prior history of breast cancer presented with a three-week history of rapidly progressive bilateral lower extremity weakness characterized by inability to walk and associated left arm radicular pain. There was no associated back or bone pain. Clinical examination revealed near complete paralysis of both lower extremities with loss of sensation below the level of the umbilicus. She had urinary incontinence, but was able to control her bowel movements. She was originally diagnosed with estrogen receptor (ER) positive T2N1M0 left-sided breast cancer 3 years previously and had a modified radical mastectomy followed by four cycles of adjuvant Adriamycin/Cyclophosphamide therapy (AC) and tamoxifen. She was doing well on tamoxifen up until 3 months prior to her current presentation, when she developed worsening back pain and was found to have disease relapse involving bone and bone marrow. She received palliative spine radiation and started on exemestane and zoledronate.
Systemic therapy, in general, has limited efficacy in the treatment of breast cancer metastasis to the central nervous system (CNS), including leptomeningeal involvement . Tamoxifen can cross the blood brain barrier and aromatase inhibitors can reduce estrogen levels in the CSF, and may therefore be reasonable additional treatment options for patients with ER-positive breast cancer and CNS metastasis [2, 3, 4]. Unfortunately, however, many patients with CNS metastases from breast cancer have ER-negative or hormone refractory disease  and would therefore not typically benefit from such therapy. Traztusumab, which is administered systemically to patients with HER2 positive disease, does not cross the blood brain barrier and the CNS is considered a sanctuary site and a common site for disease relapse in patients with HER2 positive breast cancer who were treated with traztusumab, although small tyrosine kinase inhibitors such as lapatinib may penetrate the CNS better . Traditionally, most chemotherapeutic agents used in the treatment of breast cancer do not achieve adequate CNS penetration to produce any meaningful clinical benefit, and the CNS has been well-documented as the only site of breast cancer relapse even after durable remissions from systemic chemotherapy, including with taxanes [6, 7, 8, 9]. This confirms the role of the CNS as a sanctuary site for breast cancer micrometastasis and reflects the limited penetration ability of most chemotherapy drugs across the blood brain barrier. There is some anecdotal evidence, however, suggesting that capecitabine (a 5-FU prodrug) may actually cross the blood brain barrier as evidenced by case reports of activity in patients with metastatic breast cancer to the brain [10, 11].
Our reported clinical observation is intriguing and suggests the potential for a clinically significant taxane effect in leptomeningeal metastasis from breast cancer. In this patient with no prior exposure to a taxane, there was an unexpected and dramatic complete resolution of extensive disease on MRI and relief of spinal cord compression after the administration of weekly docetaxel. The use of systemic chemotherapy in this instance was driven by the lack of feasibility of other, more standard options, such as intrathecal chemotherapy, and the choice of weekly dosing was to minimize toxicity, particularly in a patient with bone marrow metastasis. The excellent response suggests that docetaxel had to penetrate the CSF and achieve adequate levels to induce tumor regression, despite earlier published reports of poor penetrability [12, 13]. It is possible that smaller doses of chemotherapy administered more frequently in this situation may have allowed a more efficient “escape” of the drug into the CNS space than large doses given less frequently, and that would minimize excessive toxicity such as myelosuppression especially in patients such as ours with bone marrow involvement.
Another consideration beyond the ability of a chemotherapy drug to penetrate the CSF is that leptomeningeal disease is typically a late event in the course of metastatic breast cancer and therefore, lack of benefit from most systemic therapies may reflect a biologically intrinsic resistant state in the background of extensive prior therapy, rather than a routine problem with systemic drug delivery to the CNS. Indeed, the dramatic resolution of leptomeningeal disease in our case suggests that penetration to the CNS was not the problem in this instance, and drug resistant disease may indeed be an alternative explanation, as typically encountered in patients with heavily pretreated breast cancer. Analysis of breast cancer relapse patterns in the CNS following adjuvant weekly taxane use may be interesting to examine, especially knowing the superior efficacy of weekly administration schedule in preventing disease relapse over traditional scheduling . In addition, further investigation may be reasonable to verify the role of systemic chemotherapy in the treatment of CNS metastasis from breast cancer, particularly when traditional treatment approaches may not be feasible.
There are no relevant disclosures to report.