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Table 2: Overview of targeted compounds for central nervous system metastases that are outlined in the text
Molecular target Compound Compound characteristics
HER2 Trastuzumab Humanized mAb targeting the extracellular domain of HER2
Trastuzumab emantasine Antibody-drug conjugate; the antibody targeting HER2 is conjugated with
an antimicrotubule agent that is only released in HER2 target cells
+
Lapatinib Small molecule tyrosine kinase inhibitor that dually targets HER1 and
HER2, binding to the intracellular domain
Neratinib Irreversible inhibitor targeting the catalytic domain of EGRF, HER2, and
HER4
EGFR Gefitinib Inhibitor of EGFR
Erlotinib Inhibitor of EGFR
ALK Crizotinib Inhibitor of ALK
Ceritinib Inhibitor of ALK
Alectinib Inhibitor of ALK
BRAF Vemurafenib Selective inhibitor of mutated BRAF V600E
Dabrafenib Inhibitor of mutated BRAF, wild-type BRAF, and CRAF
CTLA4 Ipililumab Antibody targeting CTLA-4
PD-1 Pembrolizumab Antibody targeting PD-1 receptor
Nivolumab Antibody targeting PD-1 receptor
ALK: anaplastic lymphoma kinase; BRAF: serine/threonine-protein kinase B-Raf; CTLA: cytotoxic T-lymphocyte-associated antigen;
HER: human epidermal growth factor receptor protein; EGFR: epidermal growth factor; PD: programmed death
postoperative neurological deficit decreases survival up to CYTOTOXIC CHEMOTHERAPY: NO
3-4 months, and any substantial postoperative complication CONVENTIONAL STANDARD REGIMEN
negatively affects functional status and the patient’s ability FOR CENTRAL NERVOUS SYSTEM
to undergo subsequent radiation treatment, both of which METASTASES
are crucial factors in determining survival. [66]
To date, standard cytotoxic chemotherapy regimens have
The main modalities in radiation therapy include stereotactic not been defined for the treatment of CNS metastases.
radiotherapy and whole brain radiation therapy. Stereotactic Instead, inoperable patients are treated using the same
radiotherapy alone might be considered for patients who cytotoxic chemotherapy employed for the treatment of
have a controlled systemic disease and a limited number extracranial disease. Alternatively, cytotoxic agents with
of CNS metastases whose size is less than 3 cm. A good CNS penetration (such as topotecan, irinotecan,
combination of stereotactic and whole brain radiotherapy procarbazine, and carboplatin, temozolomide, or
has been investigated in large clinical trials. There was no fotemustine) are also employed for empirical therapy, even
difference in overall survival, but the addition of whole in cases in which these agents are not the standard therapy
brain radiation therapy significantly improved local and for the primary tumor site. Pharmacological treatments for
distant control. [9,67] Yet, patients treated with whole brain intrathecal therapies are ill-defined, too.
and stereotactic radiation therapy were at higher risk of a
decline in learning and memory. Of note, neurocognitive INTRATHECAL TREATMENT THERAPY
testing was only performed once at 4 months in this trial. FOR TARGETING THE CEREBROSPINAL
[68]
Novel concepts of whole brain radiation therapy with an FLUID
avoidance of the hippocampal region might lead to new
opportunities in this treatment modality. Intrathecal administration of drugs aims at targeting
tumor cells in the CSF efficiently by circumventing the
Radionecrosis can occur, typically within the first year blood-CSF barrier while omitting systemic toxicity.
after stereotactic radiotherapy. The differentiation between Treatment can be done by repetitive lumbar punctures
tumor progression and radionecrosis might be difficult, or through intraventricular catheter systems (i.e.,
as mentioned earlier. Treatment recommendations for Rickham or Ommaya reservoir). Among the drugs
radiosurgery radionecrosis include bevacizumab and/or available for intrathecal treatment, methotrexate (MTX)
steroids. [69] and cytarabine are most frequently used. Alternatively,
thiotriethylenephosphoramide has been approved in some
Regarding a refinement of treatment planning for radiation countries. Liposomal cytarabine is a sustained-release form
therapy, the value of amino acid PET in stereotactic of cytarabine and was compared with MTX in a controlled
radiotherapy treatment planning for focal recurrence trial in patients with solid tumors and leptomeningeal
at a previously irradiated site of a brain metastasis was carcinomatosis. Patients who were treated with liposomal
evaluated. In 88 patients, the authors found that the total cytarabine experienced a longer time until neurological
irradiation volume was significantly smaller in the PET progression. However, there was no difference in overall
group and that the median survival time was significantly survival. Liposomal cytarabine is associated with an
[71]
longer in the PET group (18.1 months) than in the MRI increased risk for radiculitis and arachnoiditis. This might
planning group (8.6 months). [70] be prevented by prophylactic dexamethasone application.

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ May 20, 2016 ¦