====== Peritumoral edema treatment ======

The use of [[corticosteroid]]s to treat cerebral [[edema]] in [[brain tumor]] patients dates back to case reports by Ingraham and Matson in [[1952]]
((Ingraham FD, Matson DD, Mc LR. Cortisone and ACTH as an adjunct to the surgery of craniopharyngiomas. N Engl J Med. 1952;246(15):568–571.)).

A few years later, a new [[corticosteroid]] with comparatively low [[mineralocorticoid]] properties and high [[glucocorticoid]] potency named [[dexamethasone]] was first synthesized
((Dietrich J, Rao K, Pastorino S, et al. Corticosteroids in brain cancer patients: benefits and pitfalls. Expert Rev Clin Pharmacol. 2011;4(2):233–242.)).

In the early 1960s, Galichich and colleagues published their experience with dexamethasone in brain tumor patients
((Galicich JH, French LA, Melby JC. Use of dexamethasone in treatment of cerebral edema associated with brain tumors. J Lancet. 1961;81:46–53. )).

Ever since, dexamethasone has been the standard corticosteroid used to treat vasogenic cerebral edema in brain tumor patients. Despite its widespread use, there are few prospective studies available to guide the optimal dosing and use of dexamethasone
((Dietrich J, Rao K, Pastorino S, et al. Corticosteroids in brain cancer patients: benefits and pitfalls. Expert Rev Clin Pharmacol. 2011;4(2):233–242.)).
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[[Dexamethasone]] (DEXA) is widely used in the management of [[peritumoral edema]]. DEXA, however, has many systemic side-effects, and may interact negatively with [[glioma]] therapy. [[Progesterone]] (PROG), on the other hand, is a well-tolerated and readily accessible [[antiinflammatory]] and anti-[[edema]] agent with potent [[neuroprotective]] properties. 

Cheng et al., investigated if PROG can serve as a viable alternative to DEXA in the management of peri-tumoral brain edema.

They used an orthotopic [[C6]] glioblastoma model with male [[Sprague Dawley rat]]s. Tumor [[graft]]s were allowed to grow for 14 days prior to [[drug]] treatment with (i) DEXA 1mg/kg, (ii) PROG 10mg/kg or (iii) PROG 20 mg/kg for five consecutive days. Overall animal survival and neurologic functions were evaluated. Mechanistic studies on [[blood brain barrier]] (BBB) permeability and angiogenic responses were performed on the ex vivo tumor grafts.

They found that all drug treatments prolonged [[overall survival]] to different extents. PROG 10mg led to significantly longer [[survival]], and better [[preservation]] of neurologic functions and body [[weight]]. [[BBB]] permeability was better preserved with PROG 10mg than DEXA possibly through the [[downregulation]] of MMP-9 and AQP-4 expressions; anti-angiogenic responses were also observed in the PROG group.

This proof-of-concept pilot study provides novel information on the use of PROG as a corticosteroids-sparing agent in brain tumor management. Further translational and clinical studies are warranted
((Cheng Y, Yeung WL, De Zhang P, Li N, Kiang MY, Leung KK. Progesterone is more 
effective than dexamethasone in prolonging overall survival and preserving
neurologic functions in experimental animals with orthotopic glioblastoma
allografts. World Neurosurg. 2019 Jan 30. pii: S1878-8750(19)30211-6. doi:
10.1016/j.wneu.2019.01.113. [Epub ahead of print] PubMed PMID: 30710720.
)).
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The [[Response Assessment in NeuroOncology]] ([[RANO]]) Working Group has developed consensus recommendations for endpoints evaluating corticosteroid use in clinical trials in both adults and children with brain tumors.

Responders are defined as patients with a 50% reduction in total daily corticosteroid dose compared with [[baseline]] or reduction of the total daily dose to ≤2 mg of dexamethasone (or equivalent dose of other corticosteroid); baseline dose must be at least 4 mg of dexamethasone daily (or equivalent dose of other corticosteroids) for at least one week. Patients must have stable or improved Neurologic Assessment in Neuro-Oncology (NANO) score or Karnofsky performance status score or Eastern Cooperative Oncology Group (ECOG) (Lansky score for children age <16 y), and an improved score on a relevant clinical outcome assessment tool. These criteria must be sustained for at least 4 weeks after baseline assessment to be considered a response, and are confirmed 4 weeks after that (ie, 8 wk after baseline assessment) to be considered a sustained response.

This RANO proposal for corticosteroid use endpoints in neuro-oncology clinical trials may need to be refined and will require prospective validation in clinical studies
((Arvold ND, Armstrong TS, Warren KE, Chang SM, DeAngelis LM, Blakeley J,
Chamberlain MC, Dunbar E, Loong HH, Macdonald DR, Reardon DA, Vogelbaum MA, Yuan 
Y, Weller M, van den Bent M, Wen PY. Corticosteroid use endpoints in
neuro-oncology: Response Assessment in Neuro-Oncology Working Group. Neuro Oncol.
2018 May 18. doi: 10.1093/neuonc/noy056. [Epub ahead of print] PubMed PMID:
29788429.
)).