Radiation necrosis treatment

Radiation necrosis treatment

Radiation necrosis (RN) will be increasingly encountered due to the widespread use of SRS. Symptomatic RN can cause significant morbidity and should be managed pro-actively. There is no single modality which can reliably distinguish RN from recurrent tumor, and a multi-modal approach is often required. For patients with symptomatic RN, oral corticosteroid therapy and bevacizumab are both effective. A minority of patients, with an unclear diagnosis, or refractory symptoms, will require surgical resection. As RN proves to be a challenging condition to diagnose and manage, risk factor mitigation becomes important in clinical decision making 1).


Using the internal database for pharmaceutical products, all patients who received BEV in the University of Munich were identified. Only patients who received BEV as symptomatic treatment for radiation necrosis were included. Patient characteristics, symptoms before, during, and after treatment, and the use of dexamethasone were evaluated using medical reports and systematic internal documentation. The symptoms were graded using CTCAE version 5.0 for general neurological symptoms. Symptoms were graded directly before each cycle and after the treatment (approximately 6 weeks). Additionally, the daily steroid dose was collected at these timepoints. Patients who either improved in symptoms, received less dexamethasone after treatment, or both were considered to have a benefit from the treatment.

Twenty-one patients who received BEV due to radiation necrosis were identified. For 10 patients (47.6%) symptoms improved and 11 patients (52.4%) remained clinically stable during the treatment. In 14 patients (66.7%) the dexamethasone dose could be reduced during therapy, 5 patients (23.8%) received the same dose of dexamethasone before and after the treatment, and 2 patients (9.5%) received a higher dose at the end of the treatment. According to this analysis, overall, 19 patients (90.5%) benefited from the treatment with BEV. No severe adverse effects were reported.

BEV might be an effective and safe therapeutic option for patients with radiation necrosis as a complication after cranial radiation therapy. Patients seem to benefit from this treatment by improving symptomatically or through reduction of dexamethasone 2).


Perez-Torres et al. validated the VEGF specificity by comparing the therapeutic efficacy of anti-VEGF with non-specific isotype control antibody. Additionally, they found that VEGF over-expression and radionecrosis developed simultaneously, which precludes preventative anti-VEGF treatment 3).

References

1)

Vellayappan B, Tan CL, Yong C, Khor LK, Koh WY, Yeo TT, Detsky J, Lo S, Sahgal A. Diagnosis and Management of Radiation Necrosis in Patients With Brain Metastases. Front Oncol. 2018 Sep 28;8:395. doi: 10.3389/fonc.2018.00395. eCollection 2018. Review. PubMed PMID: 30324090; PubMed Central PMCID: PMC6172328.
2)

Bodensohn R, Hadi I, Fleischmann DF, Corradini S, Thon N, Rauch J, Belka C, Niyazi M. Bevacizumab as a treatment option for radiation necrosis after cranial radiation therapy: a retrospective monocentric analysis. Strahlenther Onkol. 2019 Oct 4. doi: 10.1007/s00066-019-01521-x. [Epub ahead of print] PubMed PMID: 31586230.
3)

Perez-Torres CJ, Yuan L, Schmidt RE, Rich KM, Drzymala RE, Hallahan DE, Ackerman JJ, Garbow JR. Specificity of vascular endothelial growth factor treatment for radiation necrosis. Radiother Oncol. 2015 Sep 12. pii: S0167-8140(15)00462-4. doi: 10.1016/j.radonc.2015.09.004. [Epub ahead of print] PubMed PMID: 26376163.

Oral anticoagulant

Oral anticoagulant

Oral anticoagulation was first established in 1941 by Karl Paul Link, who discovered dicumarol 1).

Novel oral anticoagulants (NOAs) which directly inhibit thrombin (dabigatran) or factor Xa (rivaroxaban and apixaban) have recently been developed.

The purpose of a study was the evaluation of the reporting quality of RCTs for novel oral anticoagulants (NOACs) in venous thromboembolism (VTE) based on the CONSORT statement. MEDLINE was meticulously searched, while quoted references by retrieved RCTs were manually screened. The primary objective was to establish the mean CONSORT compliance of RCTs for NOACs in VTE. Secondary objectives were the calculation of compliance per CONSORT item and the investigation for probable determining factors with regards to the reporting quality of RCTs. Reporting above 70% of the items was defined as adequate compliance to the CONSORT statement. A total of 83 articles were considered eligible. Mean adherence to the CONSORT statement was 61.84%, standard deviation (SD) = 18.72. Among retrieved studies, 35 (42.17%) reported above 70% of the items, while 48 (57.83%) described less than 70% of the items. Inter-rater agreement was satisfactory (Cohen’s kappa ≥ 0.75). Items with respect to randomization and blinding were principally underreported, whereas the rest of the methodological features and results were more sufficiently reported. Logistic regression failed to demonstrate significant effect for any of the factors investigated. Impact factor [odds ratio (OR) = 1.347, 95% confidence interval (CI) (0.994, 1.826), p = 0.055], number of authors [OR = 1.277, 95% CI (0.975, 1.672), p = 0.076] and presentation of participant flow-diagram [OR = 55.358, 95% CI (0.914, 3351.765), p = 0.055], came closer to significance. Exploratory analysis revealed significant, strong, positive correlation between abstract and article adherence to the CONSORT guidelines (r = 0.851, p < 0.001). Reporting quality of RCTs for NOACs in VTE is moderate. A superior reporting quality is desirable, especially relating to randomization and blinding 2)

Vitamin K oral anticoagulant

Non vitamin K oral anticoagulant

Complications

Patients with minor and moderate associated bleeding can be treated with supportive care and general hemostatic measures. Nonspecific reversal agents (eg, prothrombin complex concentrate, activated prothrombin complex concentrate) are of unproven benefit, carry a risk of thrombosis, and should be reserved for severe bleeding. Specific reversal agents, such as idarucizumab (a monoclonal antibody fragment that binds dabigatran) and andexanet alfa (a recombinant factor Xa variant that binds factor Xa inhibitors but lacks coagulant activity), are in clinical development 3).

References

1)

Campbell HA, Roberts WL, Smith WK, Link KP. Studies of the hemorrhagic sweet clover disease. I. The preparation of hemorrhagic concentrates. J Biol Chem. 1940;136:47–55.
2)

Liampas I, Chlinos A, Siokas V, Brotis A, Dardiotis E. Assessment of the reporting quality of RCTs for novel oral anticoagulants in venous thromboembolic disease based on the CONSORT statement. J Thromb Thrombolysis. 2019 Aug 10. doi: 10.1007/s11239-019-01931-9. [Epub ahead of print] Review. PubMed PMID: 31401718.
3)

Cuker A, Siegal D. Monitoring and reversal of direct oral anticoagulants. Hematology Am Soc Hematol Educ Program. 2015 Dec 5;2015(1):117-24. doi: 10.1182/asheducation-2015.1.117. PubMed PMID: 26637710.

Bevacizumab for recurrent glioblastoma

Bevacizumab for recurrent glioblastoma

Bevacizumab(Avastin®)– a monoclonal antibody against VEGFFDA approved in May 2009 for progressive glioblastoma following prior treatment based on two trials: the BRAIN study, AVF3708g 1) and NCI 06-C-0064E 2).

Given as 10 mg/kg every 2 weeks until disease progression. The reported 6-month PFS rate was 36.0%. The median response durations were 3.9 months and 4.2 months from the two trials. The median OS was 9.3 months 3).

Side effects: gastrointestinal perforations, wound healing complications, hemorrhage, fistula formation, arterial thromboembolic events, hypertension.


Faltings et al. first reported the effect of rechallenging a patient with super-selective intra-arterial cerebral infusion (SIACI) of bevacizumab following disease progression after initial bevacizumab treatment and subsequent alternate clinical trial failure. There is a need to conduct further clinical trials to evaluate the benefits of rechallenge with SIACI versus IV bevacizumab for GBM, further exploring theories of bevacizumab resistance 4).


Some phase 2 trials had reported encouraging progression free survival with Bevacizumab in monotherapy or combined with chemotherapy in glioblastoma. However, phase 3 trials showed a significant improvement in progression free survival without a benefit in overall survival. To date, there are no predictive biomarker of response for Bevacizumab in glioblastoma 5)

There was interest in the role of bevacizumab, alone or in combination with cytotoxic drugs, but the results were conflicting 6) 7) 8) 9).

Given the highly vascular nature of GBM and its high expression of vascular endothelial growth factor and other angiogenic factors, recent investigation has turned to bevacizumab, an antivascular endothelial growth factor monoclonal antibody, for treatment of recurrent GBM. Phase 2 studies demonstrated the efficacy and safety of bevacizumab therapy for recurrent GBM, which led to its approval by the US Food and Drug Administration in 2009 for use in recurrent GBM. Since then, several new Phase 2 studies and retrospective series have demonstrated that bevacizumab significantly increased six-month progression-free survival in patients with recurrent GBM and may do so in new-onset GBM 10).

Further studies in recurrent disease are being conducted; preliminary results of a randomized trial showed favorable results with the combination with CCNU, and final results are awaited. Meanwhile, outside the realm of clinical trials, the current trend appears to be to reserve bevacizumab for use in recurrent disease, or for patients with moderate or severe neurologic symptoms, either in the newly diagnosed or recurrent setting. Further research efforts are needed to determine optimal candidates for this treatment from a molecular standpoint, as well as to develop imaging tools capable of accurately identifying response and progression, and to establish new drug combinations that could result in unquestionable clinical benefit and improved survival in these patients 11).

Monitoring response

In this setting, traditional anatomic MRI methods such as post-contrast T1-weighted and T2-weighted imaging are proving unreliable for monitoring response.

Standardized relative cerebral blood volume (rCBV) derived from dynamic susceptibility contrast MRI is predictive of overall survival (OS) and progression free survival (PFS) in patients with recurrent high-grade brain tumor treated with bevacizumab 12).

Overall survival

Trials on recurrent glioblastoma have shown that bevacizumab alone is able to increase response rate on MRI, median and 6-month progression-free survival (PFS), and modestly overall survival, allowing an improvement of neurological function and a reduction of steroids.

Any drug combination was not superior over bevacizumab alone. A synergistic effect of CCNU has been suggested when added to bevacizumab (BELOB trial), but excluded when added to cediranib (REGAL trial). Phase III trials on bevacizumab in newly diagnosed glioblastoma have shown an improvement of PFS of 3-4 months, but failed to prolong overall survival.

In a randomized trial of bevacizumab for newly diagnosed glioblastoma, the first-line use of bevacizumab did not improve overall survival. Progression-free survival was prolonged but did not reach the prespecified improvement target. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00884741.) 13).

Unexplained is the observation that females had longer overall survival (OS) with BEV than males in patients with progressive glioblastoma 14).

Case series

Case reports

References

1)

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 Oct 1;27(28):4733-40. doi: 10.1200/JCO.2008.19.8721. Epub 2009 Aug 31. PubMed PMID: 19720927.
2)

Kreisl TN, Kim L, Moore K, Duic P, Royce C, Stroud I, Garren N, Mackey M, Butman JA, Camphausen K, Park J, Albert PS, Fine HA. Phase II trial of single-agent bevacizumab followed by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol. 2009; 27:740–745
3)

Cohen MH, Shen YL, Keegan P, Pazdur R. FDA drug approval summary: bevacizumab (Avastin) as treatment of recurrent glioblastoma multiforme. Oncologist. 2009; 14:1131–1138
4)

Faltings L, Kulason KO, Patel NV, Wong T, Fralin S, Li M, Schneider JR, Filippi CG, Langer DJ, Ortiz R, Boockvar JA. Rechallenging Recurrent Glioblastoma with Intra-Arterial Bevacizumab with Blood Brain Barrier Disruption Results in Radiographic Response: a Case Report. World Neurosurg. 2019 Jul 24. pii: S1878-8750(19)32043-1. doi: 10.1016/j.wneu.2019.07.137. [Epub ahead of print] PubMed PMID: 31351210.
5)

Manneh Kopp RA, Sepúlveda-Sánchez JM, Ruano Y, Toldos O, Pérez Núñez A, Cantero D, Hilario A, Ramos A, de Velasco G, Sánchez-Gómez P, Hernández-Laín A. Correlation of radiological and immunochemical parameters with clinical outcome in patients with recurrent glioblastoma treated with Bevacizumab. Clin Transl Oncol. 2019 Mar 15. doi: 10.1007/s12094-019-02070-6. [Epub ahead of print] PubMed PMID: 30877636.
6)

Lombardi G, Zustovich F, Farina P, et al. Hypertension as a biomarker in patients with recurrent glioblastoma treated with antiangiogenic drugs: a single-center experience and a critical review of the literature. Anticancer Drugs. 2012;24(1):90–97.
7)

Reardon DA, Desjardins A, Peters KB, et al. Phase 2 study of carboplatin, irinotecan, and bevacizumab for recurrent glioblastoma after progression on bevacizumab therapy. Cancer. 2011;117(23):5351–5358.
8)

Zustovich F, Lombardi G, Pastorelli D, et al. Bevacizumab and glioblastomas, a single-centre experience: how disease history and characteristics may affect clinical outcome. Anticancer Research. 2010;30(12):5213–5216.
9)

Friedman HS, Prados MD, Wen PY, et al. Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. Journal of Clinical Oncology. 2009;27(28):4733–4740.
10)

Hanson JA, Hsu FP, Jacob AT, Bota DA, Alexandru D. Antivascular endothelial growth factor antibody for treatment of glioblastoma multiforme. Perm J. 2013 Fall;17(4):68-74. doi: 10.7812/TPP/13-081. PubMed PMID: 24361023; PubMed Central PMCID: PMC3854812.
11)

Thomas AA, Omuro A. Current Role of Anti-Angiogenic Strategies for Glioblastoma. Curr Treat Options Oncol. 2014 Aug 31. [Epub ahead of print] PubMed PMID: 25173555.
12)

Schmainda KM, Prah M, Connelly J, Rand SD, Hoffman RG, Mueller W, Malkin MG. Dynamic-susceptibility contrast agent MRI measures of relative cerebral blood volume predict response to bevacizumab in recurrent high-grade glioma. Neuro Oncol. 2014 Jan 15. [Epub ahead of print] PubMed PMID: 24431219.
13)

Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573. PubMed PMID: 24552317.
14)

Levin VA, Mendelssohn ND, Chan J, Stovall MC, Peak SJ, Yee JL, Hui RL, Chen DM. Impact of bevacizumab administered dose on overall survival of patients with progressive glioblastoma. J Neurooncol. 2015 Jan 11. [Epub ahead of print] PubMed PMID: 25575937.
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