Other Agents
Other agents with dual-targeting irreversible activity – such as BIBW- 299252 and HKI-27253 – have been evaluated in initial studies in solid tumours, but no data reports of its specific activity in brain metastasis are available. Canertinib (or CI-103354) is an irreversible pan-ErbB tyrosine kinase inhibitor. Targeting all four ErbB receptors has the theoretical advantage of blocking redundant signalling that might be used to bypass more specific ErbB tyrosine kinase inhibitors. However, there have been no reports of their activity in brain metastasis to date.

Other Small-molecule Agents

Sunitinib
Sunitinib is a novel, orally bio-available, multitargeted tyrosine kinase inhibitor with high binding affinity for VEGFR (types 1–3) and PDGFR (α and β), showing antitumour and antiangiogenic activities. It also inhibits FLT3, Kit (stem cell factor-receptor), colony-stimulating factor type 1 (CSF-1R) and glial cell line-derived neurotrophic factor receptor (RET) in biochemical and cellular assays.⁵⁵

Sunitinib has already been approved by the US Food and Drug Administration and the European Medicines Agency for treatment of advanced renal cell carcinoma and gastrointestinal stromal tumours in patients resistant to imatinib. Pre-clinical evaluation of its use in animal models of breast cancer provided encouraging results, showing potent antiproliferative activity either alone or in combination with 5-FU/ doxorubicin/docetaxel56 and capacity for inhibiting associated osteolysis.⁵⁷

In an open-label, single-arm, phase II trial of 64 patients with heavily pretreated metastatic disease, previously resistant to anthracyclines and taxane, sunitinib treatment resulted in an objective response rate of ~11%. Three patients (5%) had stable disease for more than six months and the overall clinical benefit was evaluated to be 16%.⁵⁸

Pre-clinical studies show that sunitinib and its metabolite penetrate the CNS with rapid clearance in mice, rats and monkeys, without any apparent accumulation. This suggests a favourable potential for antitumour activity in the brain. However, optimal target drug concentrations still have to be determined in the clinical setting.⁵⁹

Ample evidence suggests that radiation could induce tumours to produce angiogenic growth factors, which could be a mechanism of the tumour’s paracrine regulation of endothelial resistance to radiation.60 Conversely, human cells evaluated in vitro can show activation of PI3K/Akt in the absence of a growth factor stimulus, suggesting an alternative method of this pathway’s activation.^61,62 Apparently, increased doses of ionised radiation treatment of endothelial cells leads to increased phosphorylation of Akt, which plateaus at around 3Gy per dose.⁶³ The exact mechanism of how radiation activates the PI3K/Akt pathway in the absence of growth factors in endothelial cells remains to be elucidated. These cells are, however, susceptible to apoptosis in higher doses of radiation.

Tyrosine kinase receptor signalling of tumour endothelium may contribute to angiogenesis, maintenance of tumour vascular supply and, ultimately, to tumour survival and resistance to cytotoxic therapy. Because radiation therapy activates PI3/Akt signalling, the use of RTK inhibitors to block the radiation-induced activation of this pathway in the tumour vasculature has been studied.

Sunitinib has been reported to enhance radiation-induced endothelial cytotoxicity.⁶¹ Part of the response to treatment was due to increased apoptosis in endothelial cells treated with that combination, reflected by destruction of tumour vasculature in a tumour vascular window model. However, it was also noted in this study that, although the combination of treatments leads to improved tumour control, the tumours rapidly resumed growth in test animals when the therapy was discontinued.

Persistent tumour control was achieved only by adjuvant or maintenance therapy with sunitinib. One potential advantage of maintenance therapy with antiangiogenic agents is that resistance to this form of therapy does not seem to develop, perhaps because these agents target normal rather than malignant cells.64 If tumour regrowth is seen, salvage therapy by use of these agents may still be an option, because the endothelium is unlikely to develop resistance to these compounds.⁶⁵

Preliminary data from Kim and colleagues, working with mice treated with sunitinib and radiation therapy, demonstrate that even within the same animal that received systemic sunitinib, increased binding occurs only in the presence of radiotherapy. This result strongly suggests that combination therapy is important for this response.⁶⁵ Currently, ongoing clinical trials are evaluating the role of sunitinib in advanced breast cancer. Related to brain metastatic disease, a phase II clinical trial (NCT00372775) is continuing in the US and Europe, evaluating the safety and effectiveness of sunitinib associated with WBRT in non-small-cell lung-cancer patients.

Conclusions and Perspectives
The role of small molecules in the treatment of CNS metastatic disease remains to be established. There are difficulties in the evaluation of objective response by current imaging methods, which is the normal procedure to confirm activity. For patients, tumour response may be less important than restoration or preservation of neurocognitive function or quality of life, both of which are equally challenging to measure accurately and reproducibly in clinical trials.

Distinguishing tumour progression from radiation necrosis is a unique problem in CNS disease because of the difficulty in accessing tissue for definitive diagnosis.⁴ Ultimately, we may need to turn to novel imaging techniques, which could include metabolic imaging with PET, MRI etc.,⁶⁶ which is probably also the case with the targeted therapy agents.

Finally, much needs to be learned about the pathophysiology of CNS metastasis at a molecular level, and current models still have limitations, particularly related to the difficulty in accessing tissue for translational research.