Extended survival of a HER-2-positive metastatic breast cancer patient with brain metastases also treated with intrathecal trastuzumab

Excerpt

In 1991, a 38-year-old woman underwent a left mastectomy (Patey’s procedure) for stage IIA breast cancer. The histological diagnosis was ductal infiltrating carcinoma, estrogen receptor (ER) and progesterone receptor (PgR) negative, the grading and the HER-2 status unknown. She received six courses of adjuvant chemotherapy with CMF (cyclophosphamide, methotrexate and 5-fluorouracil) i.v. on days 1, 8 every 4 weeks. In September 1998 a modest increase of CA15-3 was detected and a chest and abdomen CT scan visualized three liver and one lung lesions. A biopsy of one liver lesion diagnosed metastasis of breast cancer ER and PgR negative, HER-2 3+ by immunohistochemistry (IHC). At that time trastuzumab was not approved in Italy and the patient received a first line chemotherapy with paclitaxel and doxorubicin given every 3 weeks, obtaining, after six courses, a complete remission (CR) that was consolidated with weekly trastuzumab and paclitaxel [1]. Six months later, paclitaxel was stopped and trastuzumab continued. In July 2002, the patient complained of headaches, dizziness and gait disorder and multiple brain metastases were diagnosed by MRI without evidence of other lesions (PET-CT scan negative). Whole brain radiotherapy (30 Gy in 10 fractions) was administered using 4 MV photons produced by a linear accelerator with trastuzumab on a 3-weekly schedule obtaining a partial remission (PR) of the brain lesions. In April 2003, two new brain lesions in the cerebellar lobes were diagnosed by MRI without systemic progression. The patient underwent stereotaxic radio-surgery (22 Gy) and temozolamide was added to trastuzumab. After eight courses, a CR was documented by MRI and only temozolamide was discontinued. About 8 months later a new brain lesion in the left cerebellar lobe close to the meningeal layer was diagnosed without other metastases. Temozolamide was re-started along with trastuzumab, but progression of the brain lesions was documented after 3 months. Weekly cisplatin plus capecitabine were combined to trastuzumab but her neurological conditions began to deteriorate with gait apraxia and progressive dementia due to an increase of the brain lesions but also due to the development of late effects of radiation therapy such as confluent lesions involving much of the periventricular white matter and cerebral atrophy on MRI (Fig. 1). Corticosteroids were initiated. Since the liver and lung lesions never re-appeared, this disease was considered sensitive to trastuzumab, which due to its molecular weight does not seem to pass the blood-brain barrier although, recently, it has been reported that trastuzumab levels in the cerebrospinal fluid can increase under conditions that alter the blood-brain barrier such as meningeal carcinomatosis or radiotherapy [2] Therefore, in June 2005, following the suggestion of Doctor D. J. Slamon an Ommaya ventricular catheter was inserted and intrathecal injections of trastuzumab (12.5 mg every 3 weeks) were initiated combined with intravenous trastuzumab that had never been stopped since 1999. No tumour cells were found in the cerebrospinal fluid. A stabilization of the brain lesions was obtained and corticosteroids were gradually stopped. The patient’s neurological condition improved although she requires assistance in walking and her mental status remains impaired. The treatment was continued for 19 months and 23 intrathecal injections were administered without major side effects. In February 2007, an increase of one lesion in the right cerebellar lobe and a new lesion in the right temporal lobe in contiguity to the tentorium were shown by MRI together with the stable white matter lesions. Trastuzumab was stopped and the patient was enrolled in an international extended access protocol to receive lapatinib plus capecitabine [3]. A PR has been obtained with a further slight improvement of neurological condition. In July 2008 she is still on treatment.

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