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17 references

1. Macedo LT, Lima JP, dos Santos LV, Sasse AD. Prevention strategies for chemotherapyinduced hand-foot syndrome: a systematic review and meta-analysis of prospective randomised trials. *Support Care Cancer*. 2014; 22:1585-1593.  
2. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–2005. Hinsdale, IL: CBTRUS; 2009. Available at http://www.cbtrus.org/reports/2009-NPCR-04-05/CBTRUS-NPCR2004-2005-Report-.pdf.  
3. Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI,
Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD, North American Brain Tumor C. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol. 2008; 10:162-170. PMCID: PMC2613818.  
4. Wong ET, Hess KR, Gleason MJ, Jaeckle KA, Kyritsis AP, Prados MD, Levin VA, Yung WK.  
Outcomes and prognostic factors in recurrent glioma patients enrolled onto phase II clinical trials. *J Clin Oncol*. 1999; 17:2572-2578.  
5. Wen PY, Kesari S. Malignant gliomas in adults. *N Engl J Med*. 2008; 359:492-507. 6. Friedman HS, Prados MD, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas MK, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. *J Clin Oncol*. 2009; 27:4733-4740.  
7. Park MA, Reinehr R, Haussinger D, Voelkel-Johnson C, Ogretmen B, Yacoub A, Grant S,
Dent P. Sorafenib activates CD95 and promotes autophagy and cell death via Src family kinases in gastrointestinal tumor cells. *Mol Cancer Ther*. 2010; 9:2220-2231. PMCID: PMC2933415.  
8. Park MA, Mitchell C, Zhang G, Yacoub A, Allegood J, Haussinger D, Reinehr R, Larner A,
Spiegel S, Fisher PB, Voelkel-Johnson C, Ogretmen B, Grant S, Dent P. Vorinostat and sorafenib increase CD95 activation in gastrointestinal tumor cells through a Ca(2+)-de novo ceramide-PP2A-reactive oxygen species-dependent signaling pathway. *Cancer Res*. 2010; 70:6313-6324. PMCID: PMC2918282.  
9. Cardinale D, Sandri MT, Colombo A, Colombo N, Boeri M, Lamantia G, Civelli M, Peccatori F, Martinelli G, Fiorentini C, Cipolla CM. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. *Circulation*. 2004; 109:2749-2754.  
10. Zhang G, Park MA, Mitchell C, Hamed H, Rahmani M, Martin AP, Curiel DT, Yacoub A, Graf M, Lee R, Roberts JD, Fisher PB, Grant S, Dent P. Vorinostat and sorafenib synergistically kill tumor cells via FLIP suppression and CD95 activation. *Clin Cancer Res*. 2008; 14:53855399. PMCID: PMC2561272.  
11. Duenas-Gonzalez A, Candelaria M, Perez-Plascencia C, Perez-Cardenas E, de la CruzHernandez E, Herrera LA. Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors. *Cancer Treat Rev*. 2008; 34:206-222.  
12. Venugopal B, Evans TR. Developing histone deacetylase inhibitors as anti-cancer therapeutics. *Curr Med Chem*. 2011; 18:1658-1671.  
13. Reikvam H, Ersvaer E, Bruserud O. Heat shock protein 90 - a potential target in the treatment of human acute myelogenous leukemia. *Curr Cancer Drug Targets*. 2009; 9:761776.  
14. Tang Y, Yacoub A, Hamad H, Poklepovic A, Tye G, Grant S, Dent P. Sorafenib and HDAC
inhibitors synergize to kill CNS tumor cells. *Submitted for Publication*. 2012.  
15. Black KL, Yin D, Ong JM, Hu J, Konda BM, Wang X, Ko MK, Bayan JA, Sacapano MR,
Espinoza A, Irvin DK, Shu Y. PDE5 inhibitors enhance tumor permeability and efficacy of chemotherapy in a rat brain tumor model. *Brain Res*. 2008; 1230:290-302. PMCID:
PMC2632551.  
16. Shi Z, Tiwari AK, Shukla S, Robey RW, Singh S, Kim IW, Bates SE, Peng X, Abraham I,
Ambudkar SV, Talele TT, Fu LW, Chen ZS. Sildenafil reverses ABCB1- and ABCG2mediated chemotherapeutic drug resistance. *Cancer Res*. 2011; 71:3029-3041. PMCID: PMC3078184.  
17. Agarwal S, Sane R, Ohlfest JR, Elmquist WF. The role of the breast cancer resistance protein (ABCG2) in the distribution of sorafenib to the brain. *J Pharmacol Exp Ther*. 2011; 336:223-233. PMCID: PMC3014301.  
18. Reardon DA, Vredenburgh JJ, Desjardins A, Peters K, Gururangan S, Sampson JH,
Marcello J, Herndon JE, 2nd, McLendon RE, Janney D, Friedman AH, Bigner DD, Friedman HS. Effect of CYP3A-inducing anti-epileptics on sorafenib exposure: results of a phase II
study of sorafenib plus daily temozolomide in adults with recurrent glioblastoma. J Neurooncol. 2011; 101:57-66. PMCID: PMC3102498.  
19. Zustovich F, Landi L, Lombardi G, Porta C, Galli L, Fontana A, Amoroso D, Galli C,
Andreuccetti M, Falcone A, Zagonel V. Sorafenib plus daily low-dose temozolomide for relapsed glioblastoma: a phase II study. *Anticancer Res*. 2013; 33:3487-3494.  
20. Lee EQ, Kuhn J, Lamborn KR, Abrey L, DeAngelis LM, Lieberman F, Robins HI, Chang SM,
Yung WK, Drappatz J, Mehta MP, Levin VA, Aldape K, Dancey JE, Wright JJ, Prados MD,
Cloughesy TF, Gilbert MR, Wen PY. Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05-02. *Neuro Oncol*. 2012; 14:1511-1518. PMCID: PMC3499017.  
21. Peereboom DM, Ahluwalia MS, Ye X, Supko JG, Hilderbrand SL, Phuphanich S, Nabors LB,
Rosenfeld MR, Mikkelsen T, Grossman SA, New Approaches to Brain Tumor Therapy C.  
NABTT 0502: a phase II and pharmacokinetic study of erlotinib and sorafenib for patients with progressive or recurrent glioblastoma multiforme. *Neuro Oncol*. 2013; 15:490-496.  
PMCID: PMC3607264.  
22. Galanis E, Anderson SK, Lafky JM, Uhm JH, Giannini C, Kumar SK, Kimlinger TK, Northfelt DW, Flynn PJ, Jaeckle KA, Kaufmann TJ, Buckner JC. Phase II study of bevacizumab in combination with sorafenib in recurrent glioblastoma (N0776): a north central cancer treatment group trial. *Clin Cancer Res*. 2013; 19:4816-4823. PMCID: PMC3869574.  
23. Phiel CJ, Zhang F, Huang EY, Guenther MG, Lazar MA, Klein PS. Histone deacetylase is a direct target of valproic acid, a potent anticonvulsant, mood stabilizer, and teratogen. *J Biol* Chem. 2001; 276:36734-36741.  
24. Gottlicher M, Minucci S, Zhu P, Kramer OH, Schimpf A, Giavara S, Sleeman JP, Lo Coco F,
Nervi C, Pelicci PG, Heinzel T. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. *EMBO J*. 2001; 20:6969-6978. PMCID: PMC125788.  
25. Weller M, Gorlia T, Cairncross JG, van den Bent MJ, Mason W, Belanger K, Brandes AA,
Bogdahn U, Macdonald DR, Forsyth P, Rossetti AO, Lacombe D, Mirimanoff RO, Vecht CJ, Stupp R. Prolonged survival with valproic acid use in the EORTC/NCIC temozolomide trial for glioblastoma. *Neurology*. 2011; 77:1156-1164. PMCID: PMC3265044.  
26. Guthrie GD, Eljamel S. Impact of particular antiepileptic drugs on the survival of patients with glioblastoma multiforme. *J Neurosurg*. 2013; 118:859-865.  
27. Barker CA, Bishop AJ, Chang M, Beal K, Chan TA. Valproic acid use during radiation therapy for glioblastoma associated with improved survival. *Int J Radiat Oncol Biol Phys*.  
2013; 86:504-509.  
28. Felix FHC, de Araujo OL, da Trindade KM, Trompieri NM, Fontenele JB. Survival of children with malignant brain tumors receiving valproate: a retrospective study. Childs Nervous System. 2013; 29:195-197.  
29. Kerkhof M, Dielemans JCM, van Breemen MS, Zwinkels H, Walchenbach R, Taphoorn MJ,
Vecht CJ. Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. *Neuro-Oncology*. 2013; 15:961-967.  
30. Rokes CA, Remke M, Guha-Thakurta N, Witt O, Korshunov A, Pfister S, Wolff JE. Sorafenib Plus Valproic Acid for Infant Spinal Glioblastoma. *Journal of Pediatric Hematology* Oncology. 2010; 32:511-514.  
31. Guazzi M, Vicenzi M, Arena R, Guazzi MD. Pulmonary hypertension in heart failure with preserved ejection fraction: a target of phosphodiesterase-5 inhibition in a 1-year study.  
Circulation. 2011; 124:164-174.  
32. Gomberg-Maitland M, Maitland ML, Barst RJ, Sugeng L, Coslet S, Perrino TJ, Bond L,
Lacouture ME, Archer SL, Ratain MJ. A dosing/cross-development study of the multikinase inhibitor sorafenib in patients with pulmonary arterial hypertension. *Clin Pharmacol Ther*. 2010; 87:303-310.  
33. Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W, Mariani L, Bromberg JE, Hau P, Mirimanoff RO, Cairncross JG, Janzer RC,
Stupp R. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005; 352:997-1003.  
34. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L,
Golub T, Mesirov JP, Alexe G, Lawrence M, O'Kelly M, Tamayo P, Weir BA, Gabriel S,
Winckler W, Gupta S, Jakkula L, Feiler HS, Hodgson JG, James CD, Sarkaria JN, Brennan C, Kahn A, Spellman PT, Wilson RK, Speed TP, Gray JW, Meyerson M, Getz G, Perou CM, Hayes DN. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010; 17:98-110. PMCID: PMC2818769.  
35. Simon R. Optimal two-stage designs for phase II clinical trials. *Control Clin Trials*. 1989; 10:1-10.  
36. Hutson TE, Bellmunt J, Porta C, Szczylik C, Staehler M, Nadel A, Anderson S, Bukowski R,
Eisen T, Escudier B. Long-term safety of sorafenib in advanced renal cell carcinoma: followup of patients from phase III TARGET. *Eur J Cancer*. 2010; 46:2432-2440.  
37. Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J,
Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. *J Clin Oncol*. 2010; 28:1963-1972.  
38. Macdonald DR, Cascino TL, Schold SC, Jr., Cairncross JG. Response criteria for phase II
studies of supratentorial malignant glioma. *J Clin Oncol*. 1990; 8:1277-1280.  
39. Cancer Genome Atlas Research N. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. *Nature*. 2008; 455:1061-1068. PMCID:
PMC2671642.  
40. Brookmeyer R, Crowley JJ. A confidence interval for the median survival time. *Biometrics*.  
1982; 38:29-41.  
41. Nexavar USA Prescribing Information. Bayer HealthCare Pharmaceuticals Inc.; 2011.
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appendix 1. performance status criteria

| ECOG Performance Status Scale                                                                                                                                                           | Karnofsky Performance Scale                                   |                                                                           |             |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------|---------------------------------------------------------------------------|-------------|
| Grade                                                                                                                                                                                   | Descriptions                                                  | Percent                                                                   | Description |
| 100                                                                                                                                                                                     | Normal, no complaints, no evidence  of disease.               |                                                                           |             |
| Normal activity. Fully active, able                                                                                                                                                     |                                                               |                                                                           |             |
| 0                                                                                                                                                                                       | to carry on all pre-disease  performance without restriction. | Able to carry on normal activity;                                         |             |
| 90                                                                                                                                                                                      | minor signs or symptoms of  disease.                          |                                                                           |             |
| Symptoms, but ambulatory.  Restricted in physically strenuous  activity, but ambulatory and able  to carry out work of a light or  sedentary nature (eg, light housework, office work). | 80                                                            | Normal activity with effort; some  signs or symptoms of disease.          |             |
| 1                                                                                                                                                                                       | 70                                                            | Cares for self, unable to carry on  normal activity or to do active work. |             |
| In bed < 50% of the time.  Ambulatory and capable of all selfcare, but unable to carry out any  work activities. Up and about more  than 50% of waking hours.                                                                                                                                                                                         | Requires occasional assistance, but                           |                                                                           |             |
| 60                                                                                                                                                                                      | is able to care for most of his/her  needs.                   |                                                                           |             |
| 2                                                                                                                                                                                       | 50                                                            | Requires considerable assistance  and frequent medical care.              |             |
| In bed >50% of the time. Capable  of only limited self-care, confined  to bed or chair more than 50% of  waking hours.                                                                  | 40                                                            | Disabled, requires special care and  assistance.                          |             |
| 3                                                                                                                                                                                       | 30                                                            | Severely disabled, hospitalization  indicated. Death not imminent.        |             |
| 100% bedridden. Completely  disabled. Cannot carry on any  self-care. Totally confined to bed  or chair.                                                                                | 20                                                            | Very sick, hospitalization indicated.  Death not imminent.                |             |
| 4                                                                                                                                                                                       | 10                                                            | Moribund, fatal processes  progressing rapidly.                           |             |
| 5                                                                                                                                                                                       | Dead.                                                         | 0                                                                         | Dead.       |
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appendix 2. cockcroft-gault equation

Calculated Creatinine Clearance (Cockcroft and Gault)
Creatinine Clearance (mL/min) = {(140 - Age) × Wt in kg ×
G} / (Creat × 72)
G = 1 (males); G=0.85 (females)
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appendix 3. nyha classification of

| Class   | Description                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                |
|---------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| I       | No symptoms. Ordinary physical activity such as walking and climbing stairs does not  cause fatigue or dyspnea. Symptoms with ordinary physical activity. Walking or climbing stairs rapidly, walking  uphill, walking or stair climbing after meals, in cold weather, in wind or when under  emotional stress causes undue fatigue or dyspnea. Symptoms with less than ordinary physical activity. Walking 1 to 2 blocks on the level  and climbing more than one flight of stairs in normal conditions causes undue fatigue or  dyspnea. |
| IV      | Symptoms at rest. Inability to carry on any physical activity without fatigue or dyspnea.                                                                                                                                                                                                                                                                                                                                                                                                                                                  |