title: Combining temozolomide with other antitumor drugs and target-based agents in the treatment of brain metastases: an unending quest or chasing a chimera?
abstract: BACKGROUND
  Medical treatment of brain metastases (BM) is still a controversial issue in cancer therapy being mainly limited by the existence of the BBB. Temozolomide (TMZ) can cross BBB and several clinical trials have been performed attempting to demonstrate the activity of TMZ in combination with whole brain radiotherapy (WBRT) in the treatment of BM.
  
  
  METHODS
  This review summarizes TMZ-WBRT combination trials highlighting the confounding factors that limit the interpretation of the achieved results and describes the main clinical trials using TMZ in combination with other cytotoxic or biological agents. The main limitations of these trials are: i) patient selection for heterogenous primitive neoplasms and for heterogeneous neuro-functional score; ii) poor penetration across BBB of the other drugs; iii) cumulative toxicity and iv) poor control of extracranial tumor sites.
  
  
  CONCLUSIONS
  Biotechnological, biological and biochemical advances in the management of BM could allow in short time the definition of new schedules based on the rational use of new anticancer weapons. The latter could be cytotoxic agents encapsulated in nanotechnological tools able to cross BBB, lipophilic small kinase inhibitors (lapatinib, sunitinib), mTOR inhibitors and PARP inhibitors combined with old drugs such as TMZ.
authors.affiliation: S.Giovanni di Dio Hospital, Oncology Department, Frattamaggiore, Naples, Italy. lelloaddeo@alice.it
authors.forename: Raffaele
authors.initials: R
authors.lastname: Addeo
authors.forename: Michele
authors.initials: M
authors.lastname: Caraglia
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy; D002986:Clinical Trials as Topic / Q000379:methods; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D050506:Mutant Chimeric Proteins / Q000235:genetics / Q000378:metabolism*; D000077204:Temozolomide; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D050506:Mutant Chimeric Proteins; D003606:Dacarbazine; D000077204:Temozolomide