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The role of brachytherapy in the treatment of glioblastoma multiforme

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Abstract

Brachytherapy (BT) for glioblastoma multiforme (GBM) involves the use of radioactive isotopes to deliver ionizing radiation directly into the tumor bed. Its application as a means to prolong survival in GBM patients over the past few decades has come with variable success. The objective of this review is to describe the utility of BT in GBM, and to report the outcomes and adverse events associated with its use in different multimodal treatment approaches. A search of the literature was conducted using the PubMed database. The most recent search was performed in September 2015. Thirty-two series involving 1571 patients were included in our review. The longest median overall survival (MOS) following BT for newly diagnosed GBM reached 28.5 months. Overall, 1-, 2-, and 3-year survival rates were 46–89 %, 20–57 %, and 14–27 %. For recurrent GBM, the longest reported MOS after BT was 15.9 months. One-, 2- and 3-year survival rates for recurrent GBM were 10–66 %, 3–23 %, and 9–15 %. Adverse events were reported in 27 % of patients. Reoperation for radiation necrosis occurred in 4 and 27 % of patients following low- and high-dose rate BT, respectively. BT is a feasible option for extending survival in carefully selected GBM patients. As patient outcomes and overall survival improve with more aggressive radiotherapy, so does the risk of radiation-related complications. The most effective use of BT is likely as a part of multimodal treatment with other novel therapies.

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Acknowledgments

We would like to thank Emily Yektayi for assistance in creating graphs and tables and manuscript review.

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Authors and Affiliations

  1. Department of Neurological Surgery, University of Miami Miller School of Medicine, 1095 NW 14th Terrace, 2nd Floor, Miami, FL, USA

    Eric Barbarite, Emmanuel Berchmans, Amade Bregy, Ashish H. Shah & Ricardo J. Komotar

  2. The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA

    Justin T. Sick

  3. Department of Radiation Oncology, University of Miami Miller School of Medicine, Miami, FL, USA

    Nagy Elsayyad

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  1. Eric Barbarite
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Justin Cappuzzo and Jonathan H. Sherman, Washington, USA

The authors present a literature review examining the role of brachytherapy (BT) in treatment of glioblastoma (GBM). The authors ultimately reviewed 32 manuscripts including case reports, clinical trials, and randomized control trials which included 1571 subjects specifically analyzing median overall survival (MOS) and progression-free survival (PFS) following BT in both newly diagnosed GBM and recurrent GBM. The authors also examined adverse effects following high-dose and low-dose BT. The authors found that BT may improve MOS in select patients, with the longest MOS reaching 28.5 months for newly diagnosed GBM in a trial by Chen et al., and 15.9 months for recurrent GBM in a study by Darakchiev et al. The authors also found that there was a dose–response relationship with the use of BT and recurrence of GBM; however, not surprisingly, there was an increased incidence of adverse effects at the higher dose of BT. This manuscript reviews the current literature with regard to the use of BT in treatment of GBM and organizes the findings.

Overall, the authors effectively collected and interpreted the studies regarding the role of BT in the treatment of newly diagnosed and recurrent GBM as well as adverse effects associated with both LD/HD-BT. The main weakness of this review is the lack of trials involving the use of BT in newly diagnosed GBM; however, this is to be expected as there have been few trials that have investigated this subject and the improvements that have been seen in median survival have not reached statistical significance. Additionally, the authors found that a younger patient age and a higher KPS score were positive prognostic factors in the treatment of newly diagnosed GBM with BT, as well as recurrent GBM.

One area of further investigation, as the authors already acknowledged, is the improvement of local tumor control and local recurrence control with use of BT. As the authors noted, results have largely been inconsistent; however, further development in this area may lead to decreased local tumor recurrence. Specifically, as the understanding of BT dosing improves, the balance between local tumor control and parenchymal destruction in the form of radiation necrosis will likely be improved. Additionally, as further treatments for GBM are investigated, the role that BT may have in a multimodal treatment model may be further elucidated.

Renato J. Galzio, L’Aquila, Italy.

The authors of this paper provide the first comprehensive review of the literature regarding the use of brachytherapy (BT) in the treatment of glioblastoma multiforme (GBM), with the specific objective of reporting the outcomes and the adverse events associated with its use in different multimodal treatment approaches and thereafter of assessing its possible utility and application both for newly diagnosed cases and for recurrent ones.

Study selection was accurate and comprised articles in English, published from 1990 until 2015; studies including other histological entities or not clearly reporting outcomes for GBM and BT were excluded; 35 publications were included in the final qualitative analysis and 32 in the final quantitative analysis, for a total of 1571 patients. Patients characteristics, including number of patients, median age and Karnofsky performance score (KPS) at diagnosis were analyzed and separately considered in case of newly diagnosed GBM (840 patients) or recurrent GBM (737 patients). Brachytherapy characteristics were considered including source, total dose, dose rate, planning and placement methods. Outcomes and adverse events were well categorized based on the brachytherapy source (Iodine-125 or Iridium-192) as well as on the delivered total dose and the dose rate, distinguished between low-dose rate brachytherapy (LDR-BT, characterized by delivering of less than 30 cGy/h) and high-dose rate brachytherapy (HDR-BT, characterized by delivering of more than 30 cGy/h). Association of brachytherapy with resection, external radiotherapy, chemotherapy and other adjuvant therapeutic agents, as local carmustine wafers, was also analyzed. Survival statistics considered Progression-free survival (time period from BT until first signs of tumor recurrence or progression), median overall survival (defined as the time period from diagnosis until half of the patients in a given group are still alive); when deductible from the selected studies, also in relation to KPS, percent survival time at 6 months, 1 year, 2 years, and 3 years were reported. Adverse events were evaluated whenever possible (22 studies), with special attention to radionecrosis requiring surgical solution and fatal complications directly derived from BT. The conclusion of this review is that the majority of studies report survival advantages if compared with the standard contemporary treatment and that HDR-BT results superior to LDR-BT in local tumor control, but with increased risk of radiation-related complications; thereafter, brachytherapy appears a possible adjunctive treatment option for selected patients with glioblastoma multiforme, specially for the ones with better prognostic factors (young age, good preoperative performance score, tumors in favorable areas of the brain) and less sensitive to standard chemotherapy (low expressed MGMT promoter gene).

Contemporary treatment of patients with high-grade gliomas is essentially represented by extensive surgical resection followed by external beam radiation therapy and chemotherapy with the alkylating agent temozolamide; this kind of treatment, however, remains simply palliative and no effective advancement has been accomplished in the last two decades; the median time of recurrence is almost invariably limited to less than one year and the impact of second surgery and second-line chemotherapy results also more limited in recurrences. New methods of treatment, as targeted molecular, antiangiogenic, and new chemotherapeutic agents, are under evaluation, but no consistent efficacy has been demonstrated yet.

Brachytherapy for malignant gliomas was introduced in the 1990s of the last century, but has never entered into current practice because of technical difficulties of subministration, costs, possible adverse events, and variable efficacy reported in different reports. The intrinsic suggestion emerging from this review of evaluating the reintroduction of brachytherapy for selected cases of newly diagnosed and recurrent glioblastomas appears reasonable.

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Barbarite, E., Sick, J.T., Berchmans, E. et al. The role of brachytherapy in the treatment of glioblastoma multiforme. Neurosurg Rev 40, 195–211 (2017). https://doi.org/10.1007/s10143-016-0727-6

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