Article Category: Review
Publicado en línea: 23 abr 2016
Páginas: 129 - 138
Recibido: 30 jun 2014
Aceptado: 29 sept 2014
DOI: https://doi.org/10.1515/raon-2015-0003
© 2016 Radiol Oncol
This article is distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Summary of current treatments for malignant gliomasAdditional data are from Sathornsumette et al.47, Furnari et al.48, Chi and Wen49 and Sathornsumetee et al.50 (Adapted from ref.28)
| Type of Tumour | Therapy |
|---|---|
| Newly diagnosed tumours | |
| Glioblastoma (WHO grade IV) | Maximal surgical resection, plus radiotherapy, plus concomitant and adjuvant TMZ Radiotherapy is administered at a dose of 60 Gy given in 30 fractions over a period of 6 weeks. ; Adjuvant TMZ = adjuvant temozolomide, beginning 4 weeks after radiotherapy, 150 mg/m2/day on days 1 to 5 of the first 28-day cycle, followed by 200 mg/m2/day on days 1 to 5 of each subsequent 28-day cycle, if the first cycle was well tolerated; Concomitant TMZ = concomitant temozolomide, 75 mg/m2/ day for 42 days with radiotherapy; PCV = lomustine (CCNU), 110 mg/m2, on day 1; procarbazine, 60 mg/m2 on days 8 to 21; vincristine, 1,5 mg/m2 (maximum dose, 2 mg), on days 8 and 29; WHO = World Health Organization |
| Anaplastic astrocytoma (WHO grade III) | Maximal surgical resection, with the following options after surgery (no accepted standard treatment): radiotherapy, plus concomitant and adjuvant TMZ or adjuvant TMZ alone Radiotherapy is administered at a dose of 60 Gy given in 30 fractions over a period of 6 weeks. ; Adjuvant TMZ = adjuvant temozolomide, beginning 4 weeks after radiotherapy, 150 mg/m2/day on days 1 to 5 of the first 28-day cycle, followed by 200 mg/m2/day on days 1 to 5 of each subsequent 28-day cycle, if the first cycle was well tolerated; Concomitant TMZ = concomitant temozolomide, 75 mg/m2/ day for 42 days with radiotherapy; PCV = lomustine (CCNU), 110 mg/m2, on day 1; procarbazine, 60 mg/m2 on days 8 to 21; vincristine, 1,5 mg/m2 (maximum dose, 2 mg), on days 8 and 29; WHO = World Health Organization |
| Anaplastic oligodendroglioma and anaplastic oligoastrocytoma (WHO grade III) | Maximal surgical resection, with the following options after surgery (no accepted standard treatment): radiotherapy alone, TMZ or PCV with or without radiotherapy afterward, radiotherapy plus concomitant and adjuvant TMZ, or radiotherapy plus adjuvant TMZ Radiotherapy is administered at a dose of 60 Gy given in 30 fractions over a period of 6 weeks. ; Adjuvant TMZ = adjuvant temozolomide, beginning 4 weeks after radiotherapy, 150 mg/m2/day on days 1 to 5 of the first 28-day cycle, followed by 200 mg/m2/day on days 1 to 5 of each subsequent 28-day cycle, if the first cycle was well tolerated; Concomitant TMZ = concomitant temozolomide, 75 mg/m2/ day for 42 days with radiotherapy; PCV = lomustine (CCNU), 110 mg/m2, on day 1; procarbazine, 60 mg/m2 on days 8 to 21; vincristine, 1,5 mg/m2 (maximum dose, 2 mg), on days 8 and 29; WHO = World Health Organization |
| Recurrent tumours | Reoperation in selected patients, conventional chemotherapy (e.g., lomustine, carmustine, PCV, carboplatin, irinotecan, etoposide), bevacizumab plus irinotecan, experimental therapies + |
Inherited mutation present in patients with malignant gliomas
| Syndrome | Gene name | Chromosomal location |
|---|---|---|
| Neurofibromatosis 1 | Neurofibromin 1 (NF1) | 17q11 |
| Neurofibromatosis 2 | Neurofibromin 2 (NF2) | 22q12 |
| Tuberous sclerosis | Tuberous sclerosis 1 (TSC1) Tuberous sclerosis 2 (TSC2) | 9q34 16p13 |
| Retinoblastoma | Retinoblastoma 1 (RB1) | 13q14 |
| Li-Fraumeni syndrome | Tumor suppressor p53 (TP53) | 17p13 |
| Turcot's syndrome and multiple hamartoma | Adenomatous polyposis coli (APC) DNA mismatch repair genes: Recombinant human MutL homolog-1 (hMLH2) MutS homolog 2 (hMSH2) Mismatch repair endonuclease (PMS2) Phosphatase and tensin homolog (PTEN) | 5q21 3p21.3 2p22-21 7p22 10q23.3 |
The chromosomal alterations, mostly observed in gliomas
| Chromosomal region | Type of alteration | Candidate gliomas genes |
|---|---|---|
| 1p36.31-pter | Gains and deletions | Not known |
| 1p36.22-p36.31 | Gains and deletions | Not known |
| 1p34.2-p36.1 | Gains and deletions | Not known |
| 1q32 | Gains | Receptor interacting protein kinase 5 (RIPK5), mouse double minute 4 (MDM4), phosphatidylinositol-4-phosphate 3-kinase, catalytic subunit type 2 beta (PIK3C2B) and others |
| 4q | Deletions | NIMA-related kinase 1 (NEK1), NIMA |
| 7p11.2-p12 | Amplifications or gains | |
| 9p21-p24 | Deletions | Cyclin-dependent kinase inhibitor 2A (CDKN2) |
| 10q23 | Deletions | Phosphatase and tensin homolog (PTEN) |
| 10q25-q26 | Deletions | O-6-methylguanine-DNA methyltransferase (MGMT) |
| 11p | Deletions | Between cyclin-dependent kinase inhibitor 1C (CDKN1C) and related RAS viral (r-ras) oncogene homolog 2 (RRAS2) |
| 12q13.3-q15 | Amplifications | Mouse double minute 2 homolog (MDM2), cyclin-dependent kinase 4 (CDK4) and others |
| 13p11-p13 and 13q14-q34 | Loss | Retinoblastoma 1 (RB1) |
| 19q13 | Loss | Glioma tumor suppressor candidate region gene 1 (GLTSCR1), GLTSCR2, ligase I, DNA, ATP-dependent (LIG1), cytohesin 2 (CYTH2) and many others |
| 22q11.21-q12.2 | Loss | 28 genes, including integrase interactor 1 (INI1) |
| 22q13.1-q13.3 | Loss | Not known |
Symptoms at presentation of glioblastoma
| Headache |
|---|
| Nausea/vomiting |
| Cognition changes |
| Personality changes |
| Gait imbalance |
| Urinary incontinence |
| Hemiparesis |
| Aphasia |
| Hemineglect |
| Visual field defect |
| Seizures |
Selected investigational therapies for malignant gliomasAdditional data are from Sathorsumetee et al.47, Furnari et al.48, Chi and Wen49, Sathornsumetee et al.50 ; EGFR = epidermal growth factor; FTI = farnesyltransferase; HDAC = histone deacetylase; HSP90 = heat-shock protein 90; MGMT = O6-methylguanine-DNA methyltransferase; mTOR = mammalian target of rapamycin; PARP = poly (ADP-ribose) polymerase; PDGFR = platelet-derived growth factor receptor; PI3K = phosphatidylinositol 3-kinase; PKCb = protein kinase Cb; TGF = transforming growth factor; TMZ = temozolomide; VEGFR = vascular ednosthelial growth factor receptor; WHO = World Health Organization (Adapted from ref. 28)
| Type of treatment | Example |
|---|---|
| Convection enhanced surgical delivery of pharmacologic agent | Cintredekin besudotox |
| Drugs to overcome resistance to TMZ | |
| Dose dense TMZ | O6-benzylguanine |
| MGMT inhibitors | BSI-201, ABT-888 |
| PARP inhibitors | RTA 744, ANG 1005 |
| New chemotherapies | |
| Antiangiogenic therapies | |
| Anti-avb5 integrins | Cilengitide |
| Anti-hepatocyte growth factor | AMG-102 |
| Anti-VEGF | Bevacizumab, aflibercept (VEGF-trap) |
| Anti-VEGFR | Cediranib, pazopanib, sorafenib, sunitinib, vandetinib, vatalanib, XLI 84, CT-322 |
| Other agents | Thalidomide |
| Targeted molecular therapies | |
| Akt | Perifosine |
| EGFR inhibitors | Erlotinib, gefitinib, lapatinib, BIBW2992, nimotuzumab, cetuximab |
| FTI inhibitors | Tipifarnib, lonafanib |
| HDAC inhibitors | Vorinostat, depsipeptide, LBH589 |
| HSP90 inhibitors | ATI3387 |
| Met | XLI84 |
| mTOR inhibitors | Everolimus, sirolimus, temsirolimus, deforolimus |
| PI3K inhibitors | BEZ235, XL765 |
| PKCb | Enzastaurin |
| PDGFR | inhibitors Dasatinib, imatinib, tandutinib |
| Proteasome | Bortezomib |
| Raf | Sorafenib |
| Src | Dasatinib |
| TGF | b API2009 |
| Combination therapies | Erlotinib plus temsirolimus, gefitinib plus everolimus, gefitinib plus sirolimus, saorafenib plus temsirolimus, erlotinib, or tipifarnib, pazopanib plus lapatinib |
| Immunotherapies | |
| Dendritic cell and EGFRvIII peptide vaccines | DCVax, CDX-110 |
| Monoclonal antibodies | 131I-anti-tenascin antibody |
| Gene therapy | |
| Other therapies | 131I-TM-601 |