Melphalan

Melphalan

Melphalan (trade name Alkeran, in former USSR also known as Sarcolysin) is a chemotherapy drug belonging to the class of nitrogen mustard alkylating agents.

Otherwise known as L-phenylalanine mustard, or L-PAM, melphalan is a phenylalanine derivative of mechlorethamine.


Intra-arterial Melphalan for Neurologic Non-Langerhans Cell Histiocytosis 1).


All patients with retinoblastoma treated by selective ophthalmic artery infusion chemotherapy at a single center during a 9-year period were reviewed. Only first-cycle treatments for previously untreated eyes were studied. Adjunctive factors (intra-arterial verapamil, intranasal oxymetazoline external carotid balloon occlusion) and technical factors (chemotherapy infusion time, fluoroscopy time) were documented by medical record review. Quantitative tumor reduction was determined by blinded comparison of retinal imaging acquired during examination under anesthesia before and 3-4 weeks after treatment. The dichotomous therapeutic response was classified according to quantitative tumor reduction as satisfactory (≥ 50%) or poor (<50%).

Results: Twenty-one eyes met the inclusion criteria. Patients ranged from 2 to 59 months of age. Adjuncts included intra-arterial verapamil in 15, intranasal oxymetazoline in 14, and external carotid balloon occlusion in 14. Quantitative tumor reduction ranged from 15% to 95%. Six showed poor dichotomous therapeutic response. A satisfactory dichotomous therapeutic response was correlated with intra-arterial verapamil (P = .03) in the aggregate cohort and in a subgroup undergoing treatment with single-agent melphalan at a dose of <5 mg (P = .02). In the latter, higher average quantitative tumor reduction correlated with intra-arterial verapamil (P < .01).

Conclusions: Intra-arterial verapamil during selective ophthalmic artery infusion chemotherapy is correlated with an improved therapeutic response, particularly when treating with lower doses of single-agent melphalan 2).


A phase II study explored the therapeutic gain obtained when exposing these patients to a combination of intra-arterially administered carboplatin and melphalan at first or second relapse as a salvage treatment in recurrent glioblastoma. Fifty-one consecutive patients diagnosed with glioblastoma were accrued and offered this treatment at first or second relapse. A Karnofsky score of ≥ 60 was required, and when appropriate, patients were first reoperated prior to accrual. Patients enrolled were treated every 4 weeks (1 cycle) for up to 12 cycles. Progression was evaluated by Macdonald criteria. Primary end point surrogates were overall survival from diagnosis and study entry. Median survival from diagnosis and study entry was 23 and 11 months, respectively. The median time to progression was 5.2 months. All patients enrolled were treated for a minimum of 2 cycles. Hematologic toxicity was manageable, with an 8 % of grade II neutropenia, 12 % of grade II thrombocytopenia and 7 % of grade III thrombocytopenia. This therapeutic strategy represents an adequate option in the second-line treatment of recurrent glioblastoma. The adjunction of an osmotic permeabilization could be considered to further expand delivery, and hopefully improve survival in these patients 3).


Patsalides et al describe their initial experience with a novel therapeutic approach that consists of intraarterial (IA) infusion of chemotherapy to treat progressive spinal metastases.

The main inclusion criterion was the presence of progressive, metastatic epidural disease to the spine causing spinal canal compromise in patients who were not candidates for the standard treatments of radiation therapy and/or surgery.

All tumor histological types were eligible for this trial. Using the transfemoral arterial approach and standard neurointerventional techniques, all patients were treated with IA infusion of melphalan in the arteries supplying the epidural tumor. The protocol allowed for up to 3 procedures repeated at 3- to 6-week intervals. Outcome measures included physiological measures:

1) Periprocedural complications according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events

2) MRI to assess for tumor response.

Nine patients with progressive spinal metastatic disease and cord compression were enrolled in a Phase I clinical trial of selective IA chemotherapy. All patients had metastatic disease from solid organs and were not candidates for further radiation therapy or surgery. A total of 19 spinal intraarterial chemotherapy (SIAC) procedures were performed, and the follow-up period ranged from 1 to 7 months (median 3 months). There was 1 serious adverse event (febrile neutropenia). Local tumor control was seen in 8 of 9 patients, whereas tumor progression at the treated level was seen in 1 patient.

These preliminary results support the hypothesis that SIAC is feasible and safe 4)


1)

Francis JH, Gobin YP, Nasany RA, Knopman J, Ulaner GA, Panageas K, Hatzoglou V, Salvaggio K, Abramson DH, Patsalides A, Diamond EL. Intra-arterial Melphalan for Neurologic Non-Langerhans Cell Histiocytosis. Neurology. 2021 May 12:10.1212/WNL.0000000000012070. doi: 10.1212/WNL.0000000000012070. Epub ahead of print. PMID: 33980709.
2)

Abruzzo T, Abraham K, Karani KB, Geller JI, Vadivelu S, Racadio JM, Zhang B, Correa ZM. Correlation of Technical and Adjunctive Factors with Quantitative Tumor Reduction in Children Undergoing Selective Ophthalmic Artery Infusion Chemotherapy for Retinoblastoma. AJNR Am J Neuroradiol. 2021 Jan;42(2):354-361. doi: 10.3174/ajnr.A6905. Epub 2020 Dec 24. PMID: 33361377; PMCID: PMC7872184.
3)

Fortin D, Morin PA, Belzile F, Mathieu D, Paré FM. Intra-arterial carboplatin as a salvage strategy in the treatment of recurrent glioblastoma multiforme. J Neurooncol. 2014 Sep;119(2):397-403. doi: 10.1007/s11060-014-1504-4. Epub 2014 Jun 20. PubMed PMID: 24947313.
4)

Patsalides A, Yamada Y, Bilsky M, Lis E, Laufer I, Gobin YP. Spinal intraarterial chemotherapy: interim results of a Phase I clinical trial. J Neurosurg Spine. 2015 Oct 23:1-6. [Epub ahead of print] PubMed PMID: 26496162.

Non-small cell lung cancer intracranial metastases treatment

Non-small cell lung cancer intracranial metastases treatment

Brain metastases are common in patients with non-small cell lung cancer (NSCLC). Because of associated poor prognosis and limited specific treatment options, there is a real need for the development of medical therapies and strategies for affected patients 1).


EGFR and ALK tyrosine kinase inhibitors (TKIs) provide significantly superior systemic response rates and progression free survival compared to standard chemotherapy in the molecularly defined Non-small cell lung cancer (NSCLC) subpopulations. An apparent intracranial activity of new generation TKIs triggered the discussion on their role in brain metastases in lieu of local therapies 2).

The discovery of Epidermal Growth Factor Receptor (EGFR)-activating mutations and Anaplastic Lymphoma Kinase (ALK) rearrangements in patients with non-small cell lung adenocarcinoma has allowed for the introduction of small-molecule tyrosine kinase inhibitors to the treatment of advanced-stage patients. The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein with tyrosine kinase-dependent activity. EGFR is present in membranes of all epithelial cells. In physiological conditions, it plays an important role in the process of cell growth and proliferation. Binding the ligand to the EGFR causes its dimerization and the activation of the intracellular signaling cascade. Signal transduction involves the activation of MAPKAKT, and JNK, resulting in DNA synthesis and cell proliferation. In cancer cells, binding the ligand to the EGFR also leads to its dimerization and transduction of the signal to the cell interior. It has been demonstrated that activating mutations in the gene for EGFR-exon19 (deletion), L858R point mutation in exon 21, and mutation in exon 20 results in cancer cell proliferation. Continuous stimulation of the receptor inhibits apoptosis, stimulates invasion, intensifies angiogenesis, and facilitates the formation of distant metastases. As a consequence, cancer progresses. These activating gene mutations for the EGFR are present in 10-20% of lung adenocarcinomas. Approximately 3-7% of patients with lung adenocarcinoma have the echinoderm microtubule-associated protein-like 4 (EML4)/ALK fusion gene. The fusion of the two genes EML4 and ALK results in a fusion gene that activates the intracellular signaling pathway stimulates the proliferation of tumor cells and inhibits apoptosis. A new group of drugs-small-molecule tyrosine kinase inhibitors-has been developed; the first generation includes gefitinib and erlotinib and the ALK inhibitor crizotinib. These drugs reversibly block the EGFR by stopping the signal transmission to the cell. The second-generation tyrosine kinase inhibitor (TKI) afatinib or ALK inhibitor alectinib block the receptor irreversibly. Clinical trials with TKI in patients with non-small cell lung adenocarcinoma with central nervous system (CNS) metastases have shown prolonged, progression-free survival, a high percentage of objective responses, and improved quality of life. Resistance to treatment with this group of drugs emerging during TKI therapy is the basis for the detection of resistance mutations. The T790M mutation, present in exon 20 of the EGFR gene, is detected in patients treated with first- and second-generation TKI and is overcome by Osimertinib, a third-generation TKI. The I117N resistance mutation in patients with the ALK mutation treated with alectinib is overcome by ceritinib. In this way, sequential therapy ensures the continuity of treatment. In patients with CNS metastases, attempts are made to simultaneously administer radiation therapy and tyrosine kinase inhibitors. Patients with lung adenocarcinoma with CNS metastases, without activating EGFR mutation and without ALK rearrangement, benefit from immunotherapy. This therapeutic option blocks the PD-1 receptor on the surface of T or B lymphocytes or PD-L1 located on cancer cells with an applicable antibody. Based on clinical trials, pembrolizumab and all antibodies are included in the treatment of non-small cell lung carcinoma with CNS metastases 3).


KPS score ≥ 70, RPA class I/II, and postoperative chemotherapy could benefit post-metastasectomy patients with brain metastases (BM) from Non-small cell lung cancer (NSCLC). Conversely, the initial onset of intracranial lesions is an unfavorable factor that increases the risk of death. These findings support the use of personalized therapy for patients with BM from NSCLC 4).


A article of Preusser et al., is the result of a round table discussion held at the European Lung Cancer Conference (ELCC) in Geneva in May 2017. Its purpose was to explore and discuss the advances in the knowledge about the biology and treatment of brain metastases originating from non-small cell lung cancer. The authors propose a series of recommendations for research and treatment within the discussed context 5).


PUBMEDEMBASE, the Cochrane LibraryWeb of Knowledge, Current Controlled Trials, Clinical Trials, and 2 conference websites were searched to select NSCLC patients with only single brain metastasis (SBM) who received brain surgery or SRS. SPSS 18.0 software was used to analyze the mean median survival time (MST) and Stata 11.0 software was used to calculate the overall survival (OS).

A total of 18 trials including 713 patients were systematically reviewed. The MST of the patients was 12.7 months in surgery group and 14.85 months in SRS group, respectively. The 1, 2, and 5 years OS of the patients were 59%, 33%, and 19% in surgery group, and 62%, 33%, and 14% in SRS group, respectively. Furthermore, in the surgery group, the 1 and 3 years OS were 68% and 15% in patients with controlled primary tumors, and 50% and 13% in the other patients with uncontrolled primary tumors, respectively. Interestingly, the 5-year OS was up to 21% in patients with controlled primary tumors.

There was no significant difference in MST or OS between patients treated with neurosurgery and SRS. Patients with resectable lung tumors and SBM may benefit from the resection of both primary lesions and metastasis 6).

Patients with NSCLC and synchronous brain metastases, presenting neurological symptoms showed no survival benefit from neurosurgical resection, although quality of life was improved due to early control of neurological symptoms 7).


Response rates after platinum based antineoplastics, range from 23% to 45%. Development of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs): gefitinib or erlotinib, was an improvement in treatment of advanced NSCLC patients. EGFR mutations are present in 10-25% of NSCLC (mostly adenocarcinoma), and up to 55% in never-smoking women of East Asian descent. In the non-selected group of patients with BMF-NSCLC, the overall response rates after gefitinib or erlotinib treatment range from 10% to 38%, and the duration of response ranges from 9 to 13.5 months. In the case of present activating EGFR mutation, the response rate after EGRF-TKIs is greater than 50%, and in selected groups (adenocarcinoma, patients of Asian descent, never-smokers, asymptomatic BMF-NSCLC) even 70%. Gefitinib or erlotinib treatment improves survival of BMF-NSCLC patients with EGFR mutation in comparison to cases without the presence of this mutation. There is no data on the activity of the anti-EML4-ALK agent crizotinib. Bevacizumab, recombinant humanised monoclonal antibody anti-VEGF, in the treatment of advanced non-squamous NSCLC patients is a subject of intense research. Data from a clinical trial enrolling patients with pretreated or occult BMF-NSCLC proved that the addition of bevacizumab to various chemotherapy agents or erlotinib is a safe and efficient treatment, associated with a low incidence of CSN haemorrhages. However, the efficacy and safety of bevacizumab used for therapeutic intent, regarding active brain metastases is unknown 8).

see Non small cell lung cancer intracranial metastases whole brain radiotherapy

see Non small cell lung cancer intracranial metastases radiosurgery

see Non small cell lung cancer intracranial metastases surgery.


1)

Bulbul A, Forde PM, Murtuza A, Woodward B, Yang H, Bastian I, Ferguson PK, Lopez-Diaz F, Ettinger DS, Husain H. Systemic Treatment Options for Brain Metastases from Non-Small-Cell Lung Cancer. Oncology (Williston Park). 2018 Apr 15;32(4):156-63. Review. PubMed PMID: 29684234.
2)

Wrona A, Dziadziuszko R, Jassem J. Management of brain metastases in non-small cell lung cancer in the era of tyrosine kinase inhibitors. Cancer Treat Rev. 2018 Dec;71:59-67. doi: 10.1016/j.ctrv.2018.10.011. Epub 2018 Oct 21. Review. PubMed PMID: 30366200.
3)

Rybarczyk-Kasiuchnicz A, Ramlau R, Stencel K. Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma. Int J Mol Sci. 2021 Jan 8;22(2):593. doi: 10.3390/ijms22020593. PMID: 33435596; PMCID: PMC7826874.
4)

She C, Wang R, Lu C, Sun Z, Li P, Yin Q, Liu Q, Wang P, Li W. Prognostic factors and outcome of surgically treated patients with brain metastases of non-small cell lung cancer. Thorac Cancer. 2018 Nov 28. doi: 10.1111/1759-7714.12913. [Epub ahead of print] PubMed PMID: 30485664.
5)

Preusser M, Winkler F, Valiente M, Manegold C, Moyal E, Widhalm G, Tonn JC, Zielinski C. Recent advances in the biology and treatment of brain metastases of non-small cell lung cancer: summary of a multidisciplinary roundtable discussion. ESMO Open. 2018 Jan 26;3(1):e000262. doi: 10.1136/esmoopen-2017-000262. eCollection 2018. Review. PubMed PMID: 29387475; PubMed Central PMCID: PMC5786916.
6)

Qin H, Wang C, Jiang Y, Zhang X, Zhang Y, Ruan Z. Patients with single brain metastasis from non-small cell lung cancer equally benefit from stereotactic radiosurgery and surgery: a systematic review. Med Sci Monit. 2015 Jan 12;21:144-52. doi: 10.12659/MSM.892405. PubMed PMID: 25579245.
7)

Kim SY, Hong CK, Kim TH, Hong JB, Park CH, Chang YS, Kim HJ, Ahn CM, Byun MK. Efficacy of surgical treatment for brain metastasis in patients with non-small cell lung cancer. Yonsei Med J. 2015 Jan 1;56(1):103-11. doi: 10.3349/ymj.2015.56.1.103. PubMed PMID: 25510753; PubMed Central PMCID: PMC4276743.
8)

Cedrych I, Kruczała MA, Walasek T, Jakubowicz J, Blecharz P, Reinfuss M. Systemic treatment of non-small cell lung cancer brain metastases. Contemp Oncol (Pozn). 2016;20(5):352-357. doi: 10.5114/wo.2016.64593. Epub 2016 Dec 20. Review. PubMed PMID: 28373815; PubMed Central PMCID: PMC5371701.

Steroids for chronic subdural hematoma

Since glucocorticoids have been used for treatment of chronic subdural hematoma in 1962 their role is still discussed controversially in lack of evident data. On the basis of the ascertained inflammation cycle in cSDH dexamethasone will be an ideal substance for a short lasting, concomitant treatment protocol.

Berghauser et al. stated in 2013 that the proportion of patients primarily treated with corticosteroids are increasing year by year 1)

Patients with lower grades of CSDH can be treated successfully with steroids. Female patients seem to do better with steroids 2).


In 2020 in the The New England Journal of Medicine among adults with symptomatic chronic subdural hematoma, most of whom had undergone surgery to remove their hematomas during the index admission, treatment with dexamethasone resulted in fewer favorable outcomes and more adverse events than placebo at 6 months, but fewer repeat operations were performed in the dexamethasone group. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Dex-CSDH ISRCTN number, ISRCTN80782810.) 3).

Surveys

Forty-two percent of surgeons never prescribe steroids and 55% prescribe them to those managed conservatively 4).

In another Canadian survey regarding neurosurgical practice of treatment of CSDH, <15% of neurosurgeons prefer using high-dose corticosteroid 5)

Current evidence implicates a potentially beneficial role of dexamethasone in the management of CSDH. However, it remains unclear whether the rate of crossover to surgery is reduced in patients treated with corticosteroids compared with those managed conservatively. A longer duration of study with detailed analysis of individual cases and appropriately randomized cohorts are necessary to draw more reliable conclusions 6)

Scerrati et al. performed a systematic review according to PRISMA criteria of the studies analyzing the nonsurgical strategies for CSDHs. They collected all papers in the English language published between 1990 and 2019 by searching different medical databases. The chosen keywords were “chronic subdural hematoma,” “conservative treatment/management,” “pharmacological treatment,” “non-surgical,” “tranexamic acid,” “dexamethasone,” “corticosteroid,” “glucocorticoid,” “middle meningeal artery,” “endovascular treatment,” and “embolization.”

The authors ultimately collected 15 articles regarding the pharmacological management of CSDHs matching the criteria, and 14 papers included the endovascular treatment.

The results showed that surgery still represents the mainstay in cases of symptomatic patients with large CSDHs; however, adjuvant and alternative therapies can be effective and safe in a carefully selected population. Their inclusion in new guidelines is advisable 7).


A meta-analysis of Holl et al. from 29019 suggested that the addition of corticosteroids to surgery might be effective in the treatment of CSDH. However, the results must be interpreted with caution in light of the serious risk of bias of the included studies. This study stresses the need for large randomized trials to investigate the use of corticosteroids in the management of CSDH 8)


In 2017 a study of Yao et al. had no enough evidence to support DX use as an effective alternation to surgical therapy. But adjuvant DX use may facilitate the surgical therapy by reducing chronic subdural hematoma recurrence. Further study focusing on adjuvant DX was required 9)

Among adults with symptomatic chronic subdural hematoma, most of whom had undergone surgery to remove their hematomas during the index admission, treatment with dexamethasone resulted in fewer favorable outcomes and more adverse events than placebo at 6 months, but fewer repeat operations were performed in the dexamethasone group. (Funded by the National Institute for Health Research Health Technology Assessment Programme; Dex-CSDH ISRCTN number, ISRCTN80782810.) 10).

see DECSA trial.

see SUCRE trial.

A study is designed as a double-blind randomized placebo-controlled trial 820 patients who are operated for cSDH and from the age of 25 years are included after obtaining informed consent. They are randomized for administration of dexamethasone (16-16-12-12-8-4 mg/d) or placebo (maltodextrin) during the first 48 hours after surgery. The type I error is 5% and the type II error is 20%. The primary endpoint is the reoperation within 12 weeks postoperative.

This study tests whether dexamethasone administered over 6 days is a safe and potent agent in relapse prevention for evacuated cSDH 11).

Mebberson et al. presented an interim analysis of the first registered prospective randomised placebo-controlled trial (PRPCT) of adjuvant DX on RR and outcome after CSDH surgery with post-operative drainage. Participants were randomised to either placebo or a reducing DX regime over 2 weeks, with CSDH evacuation and post-operative drainage. Post-operative mortality (POMT) and RR were determined at 30 days and 6 months; modified Rankin Score (mRS) at discharge and 6 months. Post-operative morbidity (POMB) and adverse events (AEs) were determined at 30 days. Interim analysis at approximately 50% estimated sample size was performed (n = 47). Recurrences were not observed with DX: only with placebo (0/23 [0%] v 5/24 [20.83%], P = 0.049). There was no significant between-group differences in POMT, POMB, LOS, mRS or AEs. CONCLUSIONS: In this first registered PRPCT, interim analysis suggested that adjuvant DX with post-operative drainage is both safe and may significantly decrease recurrences. A 12.5% point between-groups difference may be reasonable to power a final sample size of approximately n = 89. Future studies could consider adjuvant DX for longer than the arbitrarily-chosen 2 weeks 12).


Twenty patients with imaging-confirmed CSDH were recruited from a single center and randomized to receive dexamethasone (12 mg/day for 3 weeks followed by tapering) or placebo as a conservative treatment. Patients were followed for 6 months and the rate of success of conservative treatment with dexamethasone versus placebo was measured. Parameters such as hematoma thickness and clinical changes were also compared before and after treatment with chi-square tests. Adverse events and complications were documented.

Results: During the 6-month follow-up, one of ten patients treated with corticosteroids had to undergo surgical drainage and three of ten patients were treated surgically after placebo treatment. At the end of the study, all remaining patients had complete radiological resolution. No significant differences were observed in terms of hematoma thickness profile and impression of change; however, patients experienced more severe side effects when treated with steroids as compared with placebo. Dexamethasone contributed to many serious adverse events.

Given the small sample size, these preliminary results have not shown a clear beneficial effect of dexamethasone against placebo in our patients. However, the number of secondary effects reported was much greater for corticosteroids, and dexamethasone treatment was responsible for significant complications 13).

Sunet al. prospectively studied a group of 30 patients, who were managed non-operatively: 26 patients were treated with dexamethasone (Group 1) and four patients expectantly (Group 4). Nineteen patients (73%) from Group 1 were confused or had focal neurological deficits on admission. The mean maximum thickness of the CSDH was 12 mm. Only one of these cases (4%) required surgical drainage 6 weeks after steroid therapy. One patient died of an unrelated stroke (mortality = 4%). Two patients (8%) were left severely disabled. No significant complication from steroid therapy was documented. Out of the 85 surgically treated patients, 69 patients underwent surgical drainage in addition to steroid therapy (Group 2). Thirteen patients were treated with burr-hole drainage only (Group 3). The mean maximum thickness of the CSDH for these two groups were both 16 mm. Comparing with group 1, the redrainage rate of Group 2 [4% (3/69, p = 1)] and that of Group 3 [15% (2/13, p = 0.253)] were not significantly different. 50% of patients in Group 4 (2/4, p = 0.039) required delayed surgical drainage. The mortality rates of Groups 2, 3 and 4 were 3% (2/69, p = 1), 15% (2/13, p = 0.253) and 50% (2/4, p = 0.039), respectively. Our results suggest that steroid treatment in a selected group of patients is a good option, particularly in patients with co-morbidity 14).


1)

Berghauser Pont LM, Dippel DW, Verweij BH, Dirven CM, Dammers R. Ambivalence among neurologists and neurosurgeons on the treatment of chronic subdural hematoma: a national survey. Acta Neurol Belg. 2013 Mar;113(1):55-9. doi: 10.1007/s13760-012-0130-1. Epub 2012 Sep 14. PMID: 22975837.
2)

Thotakura AK, Marabathina NR. Nonsurgical Treatment of Chronic Subdural Hematoma with Steroids. World Neurosurg. 2015 Dec;84(6):1968-72. doi: 10.1016/j.wneu.2015.08.044. Epub 2015 Sep 2. PMID: 26342776.
3) , 10)

Hutchinson PJ, Edlmann E, Bulters D, Zolnourian A, Holton P, Suttner N, Agyemang K, Thomson S, Anderson IA, Al-Tamimi YZ, Henderson D, Whitfield PC, Gherle M, Brennan PM, Allison A, Thelin EP, Tarantino S, Pantaleo B, Caldwell K, Davis-Wilkie C, Mee H, Warburton EA, Barton G, Chari A, Marcus HJ, King AT, Belli A, Myint PK, Wilkinson I, Santarius T, Turner C, Bond S, Kolias AG; British Neurosurgical Trainee Research Collaborative; Dex-CSDH Trial Collaborators. Trial of Dexamethasone for Chronic Subdural Hematoma. N Engl J Med. 2020 Dec 31;383(27):2616-2627. doi: 10.1056/NEJMoa2020473. Epub 2020 Dec 16. PMID: 33326713.
4)

Santarius T, Lawton R, Kirkpatrick PJ, Hutchinson PJ. The management of primary chronic subdural haematoma: a questionnaire survey of practice in the United Kingdom and the Republic of Ireland. Br J Neurosurg. 2008 Aug;22(4):529-34. doi: 10.1080/02688690802195381. PMID: 18686063.
5)

Cenic A, Bhandari M, Reddy K. Management of chronic subdural hematoma: a national survey and literature review. Can J Neurol Sci. 2005 Nov;32(4):501-6. doi: 10.1017/s0317167100004510. PMID: 16408582.
6)

Petralia CCT, Manivannan S, Shastin D, Sharouf F, Elalfy O, Zaben M. Effect of Steroid Therapy on Risk of Subsequent Surgery for Neurologically Stable Chronic Subdural Hemorrhage-Retrospective Cohort Study and Literature Review. World Neurosurg. 2020 Jun;138:e35-e41. doi: 10.1016/j.wneu.2020.01.160. Epub 2020 Feb 27. PMID: 32113994.
7)

Scerrati A, Visani J, Ricciardi L, Dones F, Rustemi O, Cavallo MA, De Bonis P. To drill or not to drill, that is the question: nonsurgical treatment of chronic subdural hematoma in the elderly. A systematic review. Neurosurg Focus. 2020 Oct;49(4):E7. doi: 10.3171/2020.7.FOCUS20237. PMID: 33002869.
8)

Holl DC, Volovici V, Dirven CMF, van Kooten F, Miah IP, Jellema K, Peul WC, van der Gaag NA, Kho KH, den Hertog HM, Dammers R, Lingsma HF. Corticosteroid treatment compared with surgery in chronic subdural hematoma: a systematic review and meta-analysis. Acta Neurochir (Wien). 2019 Jun;161(6):1231-1242. doi: 10.1007/s00701-019-03881-w. Epub 2019 Apr 10. PMID: 30972566.
9)

Yao Z, Hu X, Ma L, You C. Dexamethasone for chronic subdural haematoma: a systematic review and meta-analysis. Acta Neurochir (Wien). 2017 Nov;159(11):2037-2044. doi: 10.1007/s00701-017-3309-7. Epub 2017 Sep 1. PMID: 28865006.
11)

Emich S, Richling B, McCoy MR, Al-Schameri RA, Ling F, Sun L, Wang Y, Hitzl W. The efficacy of dexamethasone on reduction in the reoperation rate of chronic subdural hematoma – the DRESH study: straightforward study protocol for a randomized controlled trial. Trials. 2014 Jan 6;15(1):6. doi: 10.1186/1745-6215-15-6. PubMed PMID: 24393328; PubMed Central PMCID: PMC3891985.
12)

Mebberson K, Colditz M, Marshman LAG, Thomas PAW, Mitchell PS, Robertson K. Prospective randomized placebo-controlled double-blind clinical study of adjuvant dexamethasone with surgery for chronic subdural haematoma with post-operative subdural drainage: Interim analysis. J Clin Neurosci. 2020 Jan;71:153-157. doi: 10.1016/j.jocn.2019.08.095. Epub 2019 Sep 3. PMID: 31492485.
13)

Prud’homme M, Mathieu F, Marcotte N, Cottin S. A Pilot Placebo Controlled Randomized Trial of Dexamethasone for Chronic Subdural Hematoma. Can J Neurol Sci. 2016 Mar;43(2):284-90. doi: 10.1017/cjn.2015.393. Epub 2016 Feb 8. PMID: 26853325.
14)

Sun TF, Boet R, Poon WS. Non-surgical primary treatment of chronic subdural haematoma: Preliminary results of using dexamethasone. Br J Neurosurg. 2005 Aug;19(4):327-33. doi: 10.1080/02688690500305332. PMID: 16455539.
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